TWI691500B

TWI691500B - Heterocycle compounds as tyro3, axl and mertk (tam) family of receptor tyrosine kinase inhibitors

Info

Publication number: TWI691500B
Application number: TW107147559A
Authority: TW
Inventors: 嚴士傑; 廖助彬; 王慧貞; 陳柏廷; 潘語之; 李從慧; 陳柏蓉; 邱顯益
Original assignee: 財團法人生物技術開發中心
Priority date: 2017-12-28
Filing date: 2018-12-28
Publication date: 2020-04-21
Also published as: CN112203659A; JP2021510729A; EP3731845A4; TW201930306A; WO2019133629A1; SG11202005983TA; WO2019133629A8; KR20200104336A; CA3086714A1; AU2018397483A1; EP3731845A1; US11407757B2; US20210009597A1

Abstract

Disclosed are compounds of formula (I) below and tautomers, stereoisomers, isotopologues, or pharmaceutically acceptable salts thereof: in which each of variables R1, ring A, L, W, V, and G is defined herein. Also disclosed are a method for treating disease or disorder mediated by Tyro3, Axl, and/or Mer kinase with a compound of formula (I) or a tautomer, stereoisomer, isotopologue, or salt thereof and a pharmaceutical composition containing same.

Description

作為TYRO3、AXL和MERTK(TAM)家族受體酪胺酸激酶抑制劑之雜環化合物 As tyro3, AXL and MERTK (TAM) family receptor tyrosine kinase Heterocyclic compounds

本發明涉及一種作為受體酪胺酸激酶抑制劑的化合物及方法。尤指一種作為受體酪胺酸激酶中TYRO3、AXL和MERTK(TAM)家族抑制劑的化合物及其醫藥組成物。 The invention relates to a compound and method as a receptor tyrosine kinase inhibitor. In particular, it refers to a compound as a TYRO3, AXL and MERTK (TAM) family inhibitor in receptor tyrosine kinase and its pharmaceutical composition.

受體酪胺酸激酶(Receptor tyrosine kinases，RTK)是一種跨膜蛋白，可將胞外環境中的信號傳導至細胞質和細胞核。受體酪胺酸激酶在調節細胞的正常運作上扮演非常重要的角色，例如，存活、生長、分化、黏附和移動。 Receptor tyrosine kinases (RTK) is a transmembrane protein that can transmit signals in the extracellular environment to the cytoplasm and nucleus. Receptor tyrosine kinase plays a very important role in regulating the normal function of cells, for example, survival, growth, differentiation, adhesion and movement.

TAM家族是一種獨特的受體酪胺酸激酶，其包括Tyro3、Axl和Mer激酶，可用以調控多種細胞功能，包括巨噬細胞(Macrophage)的凋亡(Apoptotic)、血小板的聚集作用和自然殺手細胞的分化。然而，TAM家族受體酪胺酸激酶會異位性表現或過度的大量表現在多種人類癌症中(即實質固態瘤和血液腫瘤)，目前已知與先天免疫系統和後天免疫系統的調節密切有關，可抑制腫瘤微環境下的先天免疫反應。 The TAM family is a unique receptor tyrosine kinase, which includes Tyro3, Axl and Mer kinase, can be used to regulate a variety of cellular functions, including macrophage (Macrophage) apoptosis (Apoptotic), platelet aggregation and natural killer Differentiation of cells. However, the TAM family receptor tyrosine kinase will be ectopic or excessively manifested in a variety of human cancers (ie, solid solid tumors and hematological tumors), which are currently known to be closely related to the regulation of the innate immune system and the acquired immune system , Can inhibit the innate immune response in the tumor microenvironment.

由於受體酪胺酸激酶中TAM家族的抑制可逆轉免疫抑制反應，因此，可抑制TAM家族受體酪胺酸激酶的醫藥組成物，具有潛力可用以治療與Tyro3、Axl和Mer激酶相關的各種疾病，例如癌症和炎症。 Since the inhibition of the TAM family in the receptor tyrosine kinase can reverse the immunosuppressive response, the pharmaceutical composition that can inhibit the TAM family receptor tyrosine kinase has the potential to be used to treat various types of Tyro3, Axl and Mer kinase-related Diseases, such as cancer and inflammation.

儘管各種酪胺酸激酶抑制劑被顯示為有用的治療劑，但目前仍存有低副作用之專一TAM家族酪胺酸激酶抑制劑的醫療需求。 Although various tyrosine kinase inhibitors have been shown to be useful therapeutic agents, there is still a medical need for a TAM family tyrosine kinase inhibitor with low side effects.

本發明係關於一種作為受體酪胺酸激酶抑制劑的雜環化合物。本發明之實施例係基於出人意料的發現，即某些雜環化合物相對於其他已知藥物對於如Axl與Mer受體酪胺酸激酶具有高活性。 The present invention relates to a heterocyclic compound as a receptor tyrosine kinase inhibitor. The embodiments of the present invention are based on the unexpected discovery that certain heterocyclic compounds have high activity against other known drugs such as Axl and Mer receptor tyrosine kinases.

本發明係關於一種能夠抑制激酶之化合物，具有式(I)之結構，以及式(I)所示化合物的互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類：

其中，R¹是選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；L是選自於由下列所構成的群組：氧原子、硫原子、亞胺基和芳香基；環A(

)是選自於由下列所構成的群組：

其中，當R^a和R^b兩者中的其中一個是Q時，則R^a和R^b兩者中的另一個是R²；Q是選自於由下列所構成的群組：氫原子、鹵素、OR⁵、OCH₂Ar、氰基(CN)、疊氮基(N₃)、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；R⁵和R⁶是各自獨立選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基，或是R⁵和R⁶相互連接形成碳數為3至8的環烷基或碳數為3至8的雜環烷基；R⁷是選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；Ar是選自於由下列所構成的群組：苯並二噁烷基(Benzodioxanyl)、吲唑基(Indazolyl)、異喹啉基(Isoquinolinyl)、異噁唑基(Isoxazolyl)、萘基(Naphthyl)、噁二唑基(Oxadiazolyl)、苯基(Phenyl)、吡啶基(Pyridinyl)、嘧啶基(Pyrimidinyl)、吡啶酮基(Pyridinonyl)和喹啉基(Quinolinyl)；前述Ar中的每一環上選擇性取代有一、二、三或四個取代基，取代基各自獨立選自於由下列所構成的群組：碳數為1至4的烷氧基、碳數為1至4的烷氧羰基、碳數為1至4的烷氧羰基胺基、碳數為1至4的烷基、碳數為1至4的烷羰基、碳數為1至4的烷基磺醯基、醯胺基、胺基羰基、胺基羰基(碳數為1至3的烷基)、-(CH₂)_qCO₂-(碳數為1至4的烷基)、-(CH₂)_qOH、羧基、氰基、甲醯基、鹵基、碳數為1至4的鹵代烷基、碳數為1至4的鹵代烷氧基、硝基、選擇性取代有一個氰基的苯基、選擇性取代有一個鹵基的苯氧基、苯羰基、吡咯基和四氫哌喃基；q為0、1、2、3或4；前述的碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基的一或多個部分，可各自選擇性取代有鹵素、OR⁵、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、 SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為1至8的烷氧基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；每一R²是獨立選自於由下列所構成的群組：氫原子、鹵素、羥基、甲醇基、氰基、三氟甲基、甲烷基、甲氧基、三氟甲氧基和二甲胺基；R³是選自於由下列所構成的群組：氫原子、碳數為1至4的烷基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；R⁴是選自於由下列所構成的群組：氫原子、氰基、碳數為1至4的烷基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；每一W和V各自獨立為氮原子或CR⁸，R⁸是選自於由下列所構成的群組：氫原子、鹵素、OR⁵、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁶、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；R⁵和R⁶是各自獨立選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基，或是R⁵和R⁶相互連接形成碳數為3至8的環烷基或碳數為3至8的雜環烷基；R⁷是選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；以及G是選自於由下列所構成的群組：鹵素、氰基、疊氮基、硝基、NH(R⁹)、N(R⁹)(R¹⁰)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂(R⁵)、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；每一R⁹和R¹⁰各自獨立選自於由下列所構成的群組：碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基，或是R⁹和R¹⁰相互連接形成碳數為3至8的雜環烷基；每一碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基的一或多個部分，各自可選擇性取代有由下列所構成的群組：鹵素、OR⁵、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為1至8的烷氧基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基。 The present invention relates to a compound capable of inhibiting kinases, having the structure of formula (I), and tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts of the compounds represented by formula (I):

Wherein R ¹ is selected from the group consisting of hydrogen atom, alkyl group having 1 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, heterocycloalkane having 3 to 8 carbon atoms Group, aromatic group and heteroaryl group; L is selected from the group consisting of: oxygen atom, sulfur atom, imino group and aromatic group; ring A (

) Is selected from the group consisting of:

Wherein when both R ^a and R ^b in which a is Q, then both the other of R ^a and R ^b is R ^2; Q is selected from the group consisting of the following: a hydrogen atom, Halogen, OR ⁵ , OCH ₂ Ar, cyano (CN), azido (N ₃ ), nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O )R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , alkyl having 1 to 8 carbons, alkenyl having 2 to 8 carbons, alkynyl having 2 to 8 carbons, cycloalkyl having 3 to 8 carbons, and carbon 1 Heterocycloalkyl, aryl and heteroaryl groups up to 8; R ⁵ and R ⁶ are each independently selected from the group consisting of: hydrogen atom, alkyl group having 1 to 8 carbon atoms, carbon number is 3 to 8 cycloalkyl groups, heterocyclic alkyl groups having 3 to 8 carbon atoms, aromatic groups and heteroaryl groups, or R ⁵ and R ⁶ are connected to each other to form a cycloalkyl group having 3 to 8 carbon atoms or carbon numbers Is a heterocyclic alkyl group of 3 to 8; R ⁷ is selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a carbon number Heterocycloalkyl, aromatic and heteroaryl groups of 3 to 8; Ar is selected from the group consisting of: Benzodioxanyl, Indazolyl, Isoquinoline (Isoquinolinyl), isoxazolyl (Isoxazolyl), naphthyl (Naphthyl), oxadiazolyl (Oxadiazolyl), phenyl (Phenyl), pyridyl (Pyridinyl), pyrimidinyl (Pyrimidinyl), pyridinyl (Pyridinonyl ) And Quinolinyl (Quinolinyl); one, two, three, or four substituents are optionally substituted on each ring of the aforementioned Ar, and the substituents are independently selected from the group consisting of: 4 alkoxy, alkoxycarbonyl having 1 to 4 carbons, alkoxycarbonylamino having 1 to 4 carbons, alkyl having 1 to 4 carbons, alkylcarbonyl having 1 to 4 carbons, Alkylsulfonyl, amide, aminocarbonyl, aminocarbonyl (alkyl having 1 to 3 carbons), -(CH ₂ ) _q CO ₂ -(carbon having 1 carbon) Alkyl group to 4), -(CH ₂ ) _q OH, carboxyl group, cyano group, formyl group, halo group, haloalkyl group having 1 to 4 carbon atoms, haloalkoxy group having 1 to 4 carbon atoms, nitro group , Phenyl group optionally substituted with a cyano group, phenoxy group optionally substituted with a halogen group, phenylcarbonyl group, pyrrolyl group and tetrahydropiperanyl group; q is 0, 1, 2, 3 or 4; the aforementioned C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C1-C8 heterocyclic Alkyl, aromatic and heteroaryl One or more parts can be optionally substituted with halogen, OR ⁵ , cyano, azido, nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C (O)R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , alkyl group having 1 to 8 carbons, alkoxy group having 1 to 8 carbons, alkenyl group having 2 to 8 carbons, alkynyl group having 2 to 8 carbons, carbon number Is a cycloalkyl group of 3 to 8, a heterocycloalkyl group having 1 to 8 carbon atoms, an aromatic group and a heteroaryl group; each R ² is independently selected from the group consisting of: a hydrogen atom, a halogen, Hydroxy, methanol, cyano, trifluoromethyl, methyl, methoxy, trifluoromethoxy, and dimethylamino; R ³ is selected from the group consisting of: hydrogen atom, carbon number An alkyl group of 1 to 4, a cycloalkyl group of 3 to 8 carbon atoms, a heterocycloalkyl group of 1 to 8 carbon atoms, an aromatic group and a heteroaryl group; R ⁴ is selected from the group consisting of Group: hydrogen atom, cyano group, alkyl group having 1 to 4 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, heterocycloalkyl group having 1 to 8 carbon atoms, aromatic group and heteroaryl group; each W and V are each independently a nitrogen atom or CR ⁸ , and R ⁸ is selected from the group consisting of hydrogen atom, halogen, OR ⁵ , cyano, azido, nitro, N(R ⁵ )( R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁶ , NR ⁵ SO ₂ R ⁷ , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 Alkynyl, cycloalkyl having 3 to 8 carbons, heterocycloalkyl having 1 to 8 carbons, aromatic and heteroaryl; R ⁵ and R ⁶ are each independently selected from the group consisting of Group: hydrogen atom, alkyl group having 1 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, heterocyclic alkyl group having 1 to 8 carbon atoms, aromatic group and heteroaryl group, or R ⁵ and R ^{6 is} connected to each other to form a cycloalkyl group having 3 to 8 carbon atoms or a heterocycloalkyl group having 3 to 8 carbon atoms; R ⁷ is selected from the group consisting of a hydrogen atom and a carbon number from 1 to 8 alkyl groups, cycloalkyl groups having 3 to 8 carbon atoms, heterocycloalkyl groups having 3 to 8 carbon atoms, aromatic groups and heteroaryl groups; and G is selected from the group consisting of: halogen , Cyano, azido, nitro, NH(R ⁹ ), N(R ⁹ )(R ¹⁰ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ (R ⁵ ), SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ^7. Alkenyl having 2 to 8 carbons, alkynyl having 2 to 8 carbons, cycloalkyl having 3 to 8 carbons, heterocycloalkyl having 3 to 8 carbons, aromatic groups and heteroaromatics Each R ⁹ and R ¹⁰ are independently selected from the group consisting of alkyl groups with carbon numbers 1 to 8, cycloalkyl groups with carbon numbers 3 to 8, and carbon groups with 3 to 8 Heterocycloalkyl, aromatic and heteroaryl groups, or R ⁹ and R ¹⁰ are connected to form a heterocycloalkyl group having 3 to 8 carbon atoms; each alkyl group having 1 to 8 carbon atoms and 2 carbon atoms One or more of alkenyl groups up to 8, alkynyl groups having 2-8 carbon atoms, cycloalkyl groups having 3-8 carbon atoms, heterocycloalkyl groups having 3-8 carbon atoms, aromatic groups and heteroaryl groups Part, each can be optionally substituted with a group consisting of halogen, OR ⁵ , cyano, azido, nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , alkyl group having 1 to 8 carbons, alkoxy group having 1 to 8 carbons, alkenyl group having 2 to 8 carbons, alkynyl group having 2 to 8 carbons , Cycloalkyl having 3 to 8 carbon atoms, heterocycloalkyl having 3 to 8 carbon atoms, aromatic groups and heteroaryl groups.

前述碳數為1至20的「烷基」的術語，「烷基」是指直鏈或支鏈的烴基，碳數為1至20是指碳原子數量介於1至20之間，例如：1至10或1至6。舉例來說，前述碳數為1至20的烷基可以是甲基、乙基、正丙基、異丙基、正丁基、異丁基或辛丁基。然而，本發明不以此為限。 The term "alkyl" with a carbon number of 1 to 20 refers to a linear or branched hydrocarbon group, and a carbon number of 1 to 20 refers to a number of carbon atoms between 1 and 20, for example: 1 to 10 or 1 to 6. For example, the aforementioned alkyl group having 1 to 20 carbon atoms may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or octyl. However, the invention is not limited to this.

前述碳數為2至20「烯基」的術語，是指直鏈或支鏈的烴基部分包括至少一雙鍵，例如：-CH=CH-CH₃。然而，本發明不以此為限。 The aforementioned term with a carbon number of 2 to 20 "alkenyl" refers to a straight-chain or branched hydrocarbon moiety including at least one double bond, for example: -CH=CH-CH ₃ . However, the invention is not limited to this.

前述碳數為2至20「炔基」的術語，是指直鏈或支鏈的烴基部分包括至少一三鍵，例如：-C≡C-CH₃。然而，本發明不以此為限。 The aforementioned term with a carbon number of 2 to 20 "alkynyl" refers to a straight-chain or branched-chain hydrocarbon moiety including at least one triple bond, for example: -C≡C-CH ₃ . However, the invention is not limited to this.

前述碳數為3至12「環烷基」的術語，是指碳數為3至12的飽和或部分不飽和的單環、雙環、三環或四環的烴基，碳數為3至12是指碳原子數量介於3至12之間，例如：3至10或3至8。舉例來說，前述碳數為3至12的環烷基可以是環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基或環辛基。然而，本發明不以此為限。 The term "cycloalkyl" having 3 to 12 carbon atoms refers to a saturated or partially unsaturated monocyclic, bicyclic, tricyclic or tetracyclic hydrocarbon group having 3 to 12 carbon atoms and 3 to 12 carbon atoms. Refers to the number of carbon atoms between 3 and 12, for example: 3 to 10 or 3 to 8. For example, the aforementioned cycloalkyl group having 3 to 12 carbon atoms may be cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl. However, the invention is not limited to this.

前述「雜環烷基」的術語，是指具有一或多個雜原子(例如：氧原子、氮原子、磷原子和硫原子)且碳數為5至8的單環、碳數為8至12的雙環或碳數為11至14的三環。舉例來說，雜環烷基可以是哌嗪基(Piperazinyl)、咪唑烷基(Imidazolidinyl)、氮雜環庚烷基(Azepanyl)、吡咯烷基(Pyrrolidinyl)、二氫噻二唑基(Dihydrothiadiazolyl)、二噁烷基(Dioxanyl)、嗎啉基(Morpholinyl)、四氫哌喃基(Tetrahydropyranyl)或四氫呋喃基 (Tetrahydrofuranyl)。然而，本發明不以此為限。 The aforementioned term "heterocycloalkyl" refers to a single ring having one or more heteroatoms (for example: oxygen atom, nitrogen atom, phosphorus atom and sulfur atom) and having 5 to 8 carbon atoms and 8 to 8 carbon atoms 12 is a bicyclic ring or a tricyclic ring having 11 to 14 carbon atoms. For example, the heterocycloalkyl group may be Piperazinyl, Imidazolidinyl, Azepaneyl, Pyrrolidinyl, Dihydrothiadiazolyl , Dioxanyl (Dioxanyl), Morpholinyl (Morpholinyl), Tetrahydropyranyl (Tetrahydropyranyl) or Tetrahydrofuranyl (Tetrahydrofuranyl). However, the invention is not limited to this.

前述「鹵素」的術語，是指氟、氯、溴或碘基團。前述「胺基」的術語，是指由胺衍生且未經取代、或被烷基、芳香基、環烷基、雜環烷基或雜芳基單一取代或雙取代的基團。 The aforementioned term "halogen" refers to a fluorine, chlorine, bromine or iodine group. The term "amino group" mentioned above refers to a group derived from an amine and unsubstituted, or mono- or di-substituted by an alkyl group, an aromatic group, a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group.

前述「芳香基」的術語，是指碳數為6的單環、碳數為10的雙環或碳數為14的三環芳香族系統。舉例來說，芳香基可以是苯基、萘基或蒽基。然而，本發明不以此為限。 The term "aromatic group" refers to a monocyclic ring having 6 carbon atoms, a bicyclic ring having 10 carbon atoms, or a tricyclic aromatic system having 14 carbon atoms. For example, the aromatic group may be phenyl, naphthyl or anthracenyl. However, the invention is not limited to this.

前述「雜芳基」的術語，是指具有一或多個雜原子(例如：氧原子、氮原子、磷原子和硫原子)且由5至8個原子構成的單環、由8至12個原子構成的雙環或由11至14個原子構成的三環的芳香族系統。舉例來說，雜芳基可以是***基(Triazolyl)、噁唑基(Oxazolyl)、噻二唑基(Thiadiazolyl)、四唑基(Tetrazolyl)、吡唑基(Pyrazolyl)、吡啶基(Pyridyl)、呋喃基(Furyl)、咪唑基(Imidazolyl)、苯並咪唑基(Benzimidazolyl)、嘧啶基(Pyrimidinyl)、噻吩基(Thienyl)、喹啉基(Quinolinyl)、吲哚基(Indolyl)、噻唑基(Thiazolyl)或苯並噻唑基(Benzothiazolyl)。然而，本發明不以此為限。 The aforementioned term "heteroaryl" refers to a single ring with one or more heteroatoms (for example: oxygen atom, nitrogen atom, phosphorus atom, and sulfur atom) composed of 5 to 8 atoms, consisting of 8 to 12 atoms An aromatic system consisting of a bicyclic ring of atoms or a tricyclic ring of 11 to 14 atoms. For example, the heteroaryl group may be Triazolyl, Oxazolyl, Thiadiazolyl, Tetrazolyl, Pyrazolyl, Pyridyl , Furyl, Imidazolyl, Benzimidazolyl, Pyrimidinyl, Thienyl, Quinolinyl, Indolyl, thiazolyl ( Thiazolyl) or benzothiazolyl (Benzothiazolyl). However, the invention is not limited to this.

前述烷基、烯基、炔基、環烷基、雜環烷基、芳香基和雜芳基同時包括經取代和未經取代的部分。取代基可以是烯基、炔基、環烷基、雜環烷基、芳香基和雜芳基，例如但不限於：碳數為1至10的烷基、碳數為2至10的烯基、碳數為2至10的炔基、碳數為3至20的環烷基、碳數為3至20的環烯基、碳數為1至20的雜環烷基、碳數為1至20的雜環烯基、碳數為1至10的烷氧基、芳香基、芳氧基、雜芳基、雜芳氧基、胺基、碳數為1至10的烷基胺基、碳數為1至20的二烷基胺基、芳香基胺基、二芳香基胺基、碳數為1至10的烷基磺醯胺基、芳香基磺醯胺基、碳數為1至10的亞胺基、芳香亞胺基、碳數為1至10的烷基磺醯亞胺基、芳香基磺醯亞胺基、羥基、鹵基、硫基、碳數為1至10的烷基硫基、芳香基硫基、碳數為1至10的烷基磺醯基、芳香基磺醯基、醯胺基、胺基醯基、胺基硫基醯基、胺基、脒基(Amidino)、胍(Guanidine)、脲基(Ureido)、硫脲基(Thioureido)、氰基、硝基、亞硝基、疊氮基、醯基、硫代醯基、醯氧基、羧基和羧酸酯基。另一方面，烷基上的取代基包括除了碳數為1至10的烷基之外的所有上述取代基。環烷基、雜環烷基、芳基和雜芳基也可彼此稠合。 The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic, and heteroaryl groups include both substituted and unsubstituted moieties. The substituents may be alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aromatic and heteroaryl, such as but not limited to: alkyl having 1 to 10 carbons, alkenyl having 2 to 10 carbons , An alkynyl group having a carbon number of 2 to 10, a cycloalkyl group having a carbon number of 3 to 20, a cycloalkenyl group having a carbon number of 3 to 20, a heterocycloalkyl group having a carbon number of 1 to 20, and a carbon number of 1 to Heterocyclic alkenyl of 20, alkoxy having 1 to 10 carbons, aryl, aryloxy, heteroaryl, heteroaryloxy, amine, alkylamino having 1 to 10 carbons, carbon Dialkylamine groups having 1 to 20, arylamine groups, diarylamine groups, alkylsulfonamide groups having 1 to 10 carbon atoms, aromatic sulfonamide groups, and 1 to 10 carbon atoms Imino group, aromatic imino group, alkyl sulfonylimide group having 1 to 10 carbon atoms, aromatic sulfonylimide group, hydroxyl group, halogen group, sulfur group, alkyl group having 1 to 10 carbon atoms Sulfur-based, aromatic Thio group, alkyl sulfonyl group having 1 to 10 carbons, aromatic sulfonyl group, amide group, amine group, amine sulfonyl group, amine group, amidino group, guanidine ( Guanidine), ureido (Ureido), thioureido (Thioureido), cyano, nitro, nitroso, azido, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, the substituents on the alkyl group include all the above-mentioned substituents except the alkyl group having 1 to 10 carbon atoms. Cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups can also be fused to each other.

除了上述式(I)的化合物之外，其餘藥學上可接受的鹽和溶劑化物(Solvate)也在本發明的保護範圍中。化合物可以於陰離子和帶正電荷的基團(例如胺基)之間形成鹽。適合的陰離子可以是但不限於：氯離子、溴離子、碘離子、硫酸根、硝酸根、磷酸根、檸檬酸根、甲磺酸根、三氟乙酸根、乙酸根、蘋果酸根(Malate)、甲苯磺酸根、酒石酸根(Tartrate)、Fumurate、谷胺酸根(Glutamate)、葡醣醛酸根(Glucuronate)、乳酸根(Lactate)、戊二酸根(Glutarate)和馬來酸根(Maleate)。化合物也可以在陽離子和帶負電的基團之間形成鹽。適合的陽離子可以是但不限於：鈉離子、鉀離子、鎂離子、鈣離子和銨陽離子(例如四甲基銨離子)。鹽類還進一步包括含有四級氮原子的鹽。溶劑化物是指在活性化合物和藥學上可接受的溶劑之間形成的複合物。藥學上可接受的溶劑的實例包括水、乙醇、異丙醇、乙酸乙酯、乙酸和乙醇胺。 In addition to the compound of the above formula (I), other pharmaceutically acceptable salts and solvates (Solvate) are also within the scope of protection of the present invention. Compounds can form salts between anions and positively charged groups (eg amine groups). Suitable anions can be, but are not limited to: chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate Acidate, Tartrate, Fumurate, Glutamate, Glucuronate, Lactate, Glutarate, and Maleate. Compounds can also form salts between cations and negatively charged groups. Suitable cations can be, but are not limited to: sodium ions, potassium ions, magnesium ions, calcium ions, and ammonium cations (eg, tetramethylammonium ions). Salts further include salts containing quaternary nitrogen atoms. Solvate refers to the complex formed between the active compound and a pharmaceutically acceptable solvent. Examples of pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid, and ethanolamine.

本發明之另一態樣係一種醫藥組成物，其可用以治療與受體酪胺酸激酶相關的疾病，例如癌症和炎症。 Another aspect of the invention is a pharmaceutical composition that can be used to treat diseases associated with receptor tyrosine kinases, such as cancer and inflammation.

醫藥組成物包括前述式(I)的化合物或其互變異構物、立體異構物、同位素異構物與藥學可接受的鹽類，以及一藥學可接受的載體。 The pharmaceutical composition includes the compound of the aforementioned formula (I) or tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

本發明也涵蓋了這種組合物在製備用於治療TAM家族受體酪胺酸激酶相關疾病或失調的藥品之用途。 The invention also covers the use of this composition in the preparation of a medicament for the treatment of diseases or disorders associated with TAM family receptor tyrosine kinase.

用於口服給藥的醫藥組合物可以是任何口服可接受的劑型，包括膠囊、片劑、乳劑、水性懸浮液、分散體和溶液。在片劑的情況下，常用的載體包括乳糖和玉米澱粉，且通常另添加潤滑劑，例如硬脂酸鎂。對於膠囊形式的口服藥劑，可用的稀釋劑包括乳糖和乾玉米澱粉。當使用懸浮液或乳液作為口服藥劑時，活性成分會懸浮或溶解於乳化懸浮的油相中，並可依需求另外添加某些甜味劑、調味劑或著色劑。口服固體劑型的製備方式可以利用噴霧乾燥法、熱熔擠出法、微粉化和奈米研磨的技術。 The pharmaceutical composition for oral administration may be in any orally acceptable dosage form, including capsules, tablets, emulsions, aqueous suspensions, dispersions, and solutions. In the case of tablets, commonly used The body includes lactose and corn starch, and usually additional lubricants, such as magnesium stearate. For oral agents in capsule form, useful diluents include lactose and dried corn starch. When a suspension or emulsion is used as an oral agent, the active ingredient will be suspended or dissolved in the emulsified suspended oil phase, and certain sweeteners, flavoring agents, or colorants may be additionally added as required. Oral solid dosage forms can be prepared by spray drying, hot melt extrusion, micronization, and nanogrinding techniques.

根據藥物製劑領域熟知的技術，前述化合物和醫藥組成物亦可製備成鼻氣霧劑或吸入組合物。舉例來說，這種組合物可以製備成以矽烷保存的溶液，或是使用芐醇或是其它合適的防腐劑、吸收促進劑、碳氟化合物和/或本領域已知的其它增溶劑或分散劑。具有活性化合物的醫藥組合物也可以栓劑的形式給藥，例如直腸給藥。 According to techniques well known in the field of pharmaceutical formulations, the aforementioned compounds and pharmaceutical compositions can also be prepared as nasal aerosols or inhalation compositions. For example, this composition can be prepared as a solution preserved in silane, or using benzyl alcohol or other suitable preservatives, absorption enhancers, fluorocarbons, and/or other solubilizers or dispersions known in the art Agent. Pharmaceutical compositions with active compounds can also be administered in the form of suppositories, such as rectal administration.

藥物組合物中的載體必須是「可接受的」，即活性成分(化合物)可與之相容(並且優選地，能夠穩定活性成分)，且活性成分與載體的組合物對於治療的受試者無害。一種或多種增溶劑可用作藥物賦形劑，以遞送活性化合物。其他載體的實例包括膠體氧化矽、硬脂酸鎂、纖維素、十二烷基硫酸鈉和D & C黃# 10。 The carrier in the pharmaceutical composition must be "acceptable", that is, the active ingredient (compound) is compatible with it (and preferably, capable of stabilizing the active ingredient), and the combination of the active ingredient and the carrier is for the treated subject harmless. One or more solubilizers can be used as pharmaceutical excipients to deliver the active compound. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and D & C Yellow #10.

本發明的範圍仍然是治療TAM家族受體酪胺酸激酶相關疾病的方法。前述治療方法包括向一受試者施以一有效劑量包含式(I)的化合物及其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類的醫藥組成物。 The scope of the present invention is still a method for treating TAM family receptor tyrosine kinase-related diseases. The aforementioned method of treatment includes administering to a subject an effective dose of a pharmaceutical composition comprising the compound of formula (I) and its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts.

上述化合物或醫藥組成物可以通過口服、腸胃外、噴霧吸入、局部、直腸、鼻腔、口腔或植入的方式給予受試者。本發明中「腸胃外」的術語，包括於皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內和顱內注射或輸注。 The above compound or pharmaceutical composition can be administered to a subject by oral, parenteral, spray inhalation, topical, rectal, nasal, oral, or implantation. The term "parenteral" in the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion.

本發明中「治療」的術語，是指將化合物施用於受試者以治癒、減輕、緩解、改變、補救、改善或影響疾病的症狀或傾向。「有效量」是指賦予受試者達到所需效果所需的化合物的量。如所屬技術領域的通常知識者所知，有效量會根據給藥途徑、賦形劑使用方式以及搭配的其他治療(例如使用其他活性劑)而有所不同。 The term "treatment" in the present invention refers to administration of a compound to a subject to cure, alleviate, alleviate, alter, remedy, ameliorate, or affect the symptoms or tendency of the disease. "Effective amount" refers to the endowment The amount of compound needed to give the subject the desired effect. As known to those of ordinary skill in the art, the effective amount will vary depending on the route of administration, the mode of use of the excipients, and other treatments (eg, the use of other active agents).

在下面的描述中闡述了本發明的一個或多個實施方案的細節。根據說明書和請求項的內容，本發明的其他特徵，目的和優點將顯而易見。 The details of one or more embodiments of the invention are set forth in the description below. Other features, purposes, and advantages of the present invention will be apparent from the contents of the description and the claims.

本發明的其中一有益效果在於，本發明所提供的作為受體酪胺酸激酶抑制劑的醫藥組成物及其化合物，其能通過“如式(I)所示的化合物或其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類”的技術方案，以有效抑制受體酪胺酸激酶中的TAM家族(TYRO3、AXL和MERTK激酶)。 One of the beneficial effects of the present invention is that the pharmaceutical composition and the compound thereof as receptor tyrosine kinase inhibitors provided by the present invention can pass through the compound represented by formula (I) or its tautomer , Stereoisomers, isotopic isomers and pharmaceutically acceptable salts" technical solutions to effectively inhibit the TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK kinases).

為使能更進一步瞭解本發明的特徵及技術內容，請參閱以下有關本發明的詳細說明，然而所提供的參考與說明並非用來對本發明加以限制。 In order to further understand the features and technical content of the present invention, please refer to the following detailed description of the present invention, but the provided references and descriptions are not intended to limit the present invention.

以下是通過特定的具體實施例來說明本發明所公開有關“作為TYRO3、AXL和MERTK(TAM)家族受體酪胺酸激酶抑制劑之雜環化合物”的實施方式，本領域技術人員可由本說明書所公開的內容瞭解本發明的優點與效果。本發明可通過其他不同的具體實施例加以施行或應用，本說明書中的各項細節也可基於不同觀點與應用，在不悖離本發明的構思下進行各種修改與變更。 The following are specific specific examples to illustrate the embodiments of the present invention related to "heterocyclic compounds as tyro3, AXL and MERTK (TAM) family receptor tyrosine kinase inhibitors". The disclosed content understands the advantages and effects of the present invention. The present invention can be implemented or applied through other different specific embodiments. Various details in this specification can also be based on different viewpoints and applications, and various modifications and changes can be made without departing from the concept of the present invention.

應當可以理解的是，本文中所使用的術語“或”，應視實際情況可能包括相關聯的列出項目中的任一個或者多個的組合。 It should be understood that the term "or" as used herein may include any combination of any one or more of the associated listed items, depending on the actual situation.

本發明公開一種以式(I)表示化合物：

以及其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類化合物。式(I)中的R¹、環A(即

)、L、W、V和G定義於發明內容中。 The invention discloses a compound represented by formula (I):

And its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salt compounds. R ¹ in formula (I), ring A (ie

), L, W, V and G are defined in the summary of the invention.

於式(I)中，L較佳為氧原子，G較佳為N(R⁹)(R¹⁰)或碳數為3至8的雜環烷基。 In formula (I), L is preferably an oxygen atom, and G is preferably N(R ⁹ )(R ¹⁰ ) or a heterocyclic alkyl group having 3 to 8 carbon atoms.

當G是N(R⁹)(R¹⁰)時，每一R⁹和R¹⁰各自獨立選自於由下列所構成的群組：碳數為1至8的烷基、碳數為3至8的環烷基和碳數為3至8的雜環烷基，或是R⁹和R¹⁰相互連接形成碳數為1至8的雜環烷基。 When G is N(R ⁹ )(R ¹⁰ ), each R ⁹ and R ¹⁰ are independently selected from the group consisting of alkyl groups with carbon numbers from 1 to 8 and carbon numbers from 3 to 8 Cycloalkyl group and heterocyclic alkyl group having 3 to 8 carbon atoms, or R ⁹ and R ¹⁰ are connected to each other to form a heterocyclic alkyl group having 1 to 8 carbon atoms.

於其中一實施例，於式(I)中，G是-N(R⁹)(R¹⁰)，R⁹和R¹⁰相互連接形成碳數為3至8的雜環烷基。舉例來說，G可以是

，G選擇性取代有一或多個碳數為1至8的烷基。Y可以是氧原子、-NR或-CR'R"；R、R'和R"各自獨立選自於由下列所構成的群組：氫原子、羥基、胺基或碳數為1至8的烷基。較佳的，Y是-NR，且R是氫原子或碳數為1至8的烷基。或者，Y是-CR'R"，且R'和R"各自獨立為氫原子、羥基、胺基或碳數為1至8的烷基。具體而言，化合物可表示如下：

W和V各自獨立為氮原子或-CR⁸，R⁸可以是氫原子、鹵素、OR⁵、N(R⁵)(R⁶) 或碳數為1至8的烷基。包含Y的雜環可選擇性取代有一或多個碳數為1至8的烷基。當G為碳數為3至8的雜環時，碳數為3至8的雜環較佳是一五環結構或一六環結構。五環結構或六環結構可以是選自於由下列所構成的群組，但不限於：

In one embodiment, in formula (I), G is -N(R ⁹ )(R ¹⁰ ), and R ⁹ and R ¹⁰ are connected to each other to form a heterocycloalkyl group having 3 to 8 carbon atoms. For example, G can be

, G is optionally substituted with one or more alkyl groups having 1 to 8 carbon atoms. Y may be an oxygen atom, -NR or -CR 'R "; R, R ' and R" are each independently selected from the group consisting of the following: a hydrogen atom, a hydroxyl group or a C number of 1 to 8, alkyl. Preferably, Y is -NR, and R is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. Alternatively, Y is -CR 'R ", and R' and R" are each independently a hydrogen atom, a hydroxyl group, amine or alkyl having 1 to 8. Specifically, the compound can be expressed as follows:

W and V are each independently a nitrogen atom or -CR ⁸ , and R ⁸ may be a hydrogen atom, halogen, OR ⁵ , N(R ⁵ )(R ⁶ ), or an alkyl group having 1 to 8 carbon atoms. The heterocyclic ring containing Y can be optionally substituted with one or more alkyl groups having 1 to 8 carbon atoms. When G is a heterocyclic ring having 3 to 8 carbon atoms, the heterocyclic ring having 3 to 8 carbon atoms is preferably a five-ring structure or a six-ring structure. The five-ring structure or the six-ring structure may be selected from the group consisting of, but not limited to:

於式(I)中，環A較佳為一芳香基。例如，環A可以是未經取代或是一至三個部分具有取代基的苯基，取代基可以是選自於由下列所構成的群組：鹵素、OR⁵、OCH₂Ar、氰基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂N(R⁵)(R⁶)、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為3至8的環烷基和碳數為3至8的雜環烷基。R¹較佳為碳數為1至8的烷基、碳數為3至8的環烷基或碳數為3至8的雜環烷基。舉例來說，碳數為1至8的烷基可以選擇性取代有碳數為1至8的烷氧基、碳數為3至8的環烷基、碳數為3至8的雜環烷基或雜芳基。 In formula (I), ring A is preferably an aromatic group. For example, ring A may be unsubstituted or a phenyl group having one to three parts having a substituent, and the substituent may be selected from the group consisting of halogen, OR ⁵ , OCH ₂ Ar, cyano, N (R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ N(R ⁵ )(R ⁶ ), NR ⁵ SO ₂ R ⁷ , alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons, and heterocycloalkyl having 3 to 8 carbons. R ^{1 is} preferably an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a heterocyclic alkyl group having 3 to 8 carbon atoms. For example, an alkyl group having 1 to 8 carbon atoms may be optionally substituted with an alkoxy group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, and a heterocycloalkane having 3 to 8 carbon atoms. Radical or heteroaryl.

於一些實施例中，式(I)中化合物的環A的是具有一至三個取代基取代的苯基，取代基是選自於由下列所構成的群組：鹵素、OR⁵、OCH₂Ar、氰基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂N(R⁵)(R⁶)、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基。R¹是碳數為1至8的烷基，且可選擇性經碳數為1至8的烷氧基、碳數為3至8的環烷基、碳數為3至8的雜環烷基或雜芳基取代。L是氧原子。G是N(R⁹)(R¹⁰)，R⁹和R¹⁰相互連接形成碳數為3至8的雜環烷基。於一些實施例中，化合物可表示如下：

In some embodiments, the ring A of the compound of formula (I) is a phenyl group substituted with one to three substituents, the substituents are selected from the group consisting of halogen, OR ⁵ , OCH ₂ Ar , Cyano, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ N( R ⁵ )(R ⁶ ), NR ⁵ SO ₂ R ⁷ , alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons, and heterocycloalkyl having 3 to 8 carbons. R ¹ is an alkyl group having 1 to 8 carbon atoms, and can be optionally selected from alkoxy groups having 1 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, and heterocycloalkanes having 3 to 8 carbon atoms. Group or heteroaryl substitution. L is an oxygen atom. G is N(R ⁹ )(R ¹⁰ ), and R ⁹ and R ¹⁰ are connected to each other to form a heterocyclic alkyl group having 3 to 8 carbon atoms. In some embodiments, the compound may be represented as follows:

其中，W和V各自獨立為氮原子或CR⁸，R⁸是選自由下列所構成的群組：氫原子、鹵素、OR⁵、N(R⁵)(R⁶)和碳數為1至8的烷基。Y是氧原子、-NR或-CR'R"；R、R'和R"各自獨立選自於由下列所構成的群組：氫原子、羥基、胺基或碳數為1至8的烷基。包含Y的雜環可選擇性取代有一或多個碳數為1至8的烷基。 Wherein, W and V are each independently a nitrogen atom or CR ⁸ , and R ⁸ is selected from the group consisting of hydrogen atom, halogen, OR ⁵ , N(R ⁵ )(R ⁶ ) and carbon number 1 to 8. Of alkyl. Y is an oxygen atom, -NR or -CR 'R "; R, R ' and R" are each independently selected from the group consisting of the following: a hydrogen atom, a hydroxyl group, an alkoxy group or a C number of 1 to 8 base. The heterocyclic ring containing Y can be optionally substituted with one or more alkyl groups having 1 to 8 carbon atoms.

於式(I)中，變數R¹、環A、L和G各自包括其R型或S型的立體異構物，且每一化合物的鏡像異構物過量值(Enantiomeric excess)為90%或更高，例如：大於或等於95%或大於或等於99%。然而，本發明不以此為限。 In formula (I), the variables R ¹ , rings A, L and G each include their R- or S-type stereoisomers, and the enantiomeric excess value of each compound is 90% or Higher, for example: greater than or equal to 95% or greater than or equal to 99%. However, the invention is not limited to this.

另外，本發明提供一種醫藥組成物，其可用以治療癌症，例如實質固態瘤和血液腫瘤。醫藥組成物包括式(I)中的化合物，或其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類中的其中一種，以及一藥學可接受的載體。 In addition, the present invention provides a pharmaceutical composition that can be used to treat cancer, such as parenchymal solid tumors and hematological tumors. The pharmaceutical composition includes the compound of formula (I), or one of its tautomers, stereoisomers, isotopic isomers, and pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

此外，本發明另提供一種與TAM家族受體酪胺酸激酶相關的疾病的治療方法，上述方法包括向一受試者施以一有效劑量如式(I)所示的化合物，或其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類中的其中一種。 In addition, the present invention also provides a method for treating diseases associated with the TAM family receptor tyrosine kinase. The above method includes administering an effective dose of a compound represented by formula (I) to a subject, or a mutual variation thereof One of a structure, a stereoisomer, an isotopic isomer, and a pharmaceutically acceptable salt.

可以上述治療方法治療的疾病可以是與TAM家族受體酪胺酸激酶(即Tyro3、Axl和Mer激酶)相關癌症或炎症。以下將詳述上述三激酶以及關於其致病的機制。 The diseases that can be treated by the above treatment methods may be cancer or inflammation associated with TAM family receptor tyrosine kinases (ie, Tyro3, Axl, and Mer kinases). The above-mentioned trikinase and its pathogenic mechanism will be described in detail below.

Tyro3(又稱為Brt、Dtk、Etk-2、Rek、Rse、Sky或Tif)主要表現於腦部和中樞神經系統(Central nervous system，CNS)，且顯示與腫瘤發生和腫瘤細胞的存活有關。因此，Tyro3可作為治療劑辨識的標靶，以治療Tyro3過度表現造成的癌症(例如膀胱癌、黑素瘤和乳腺癌)或用於增強免疫反應。 Tyro3 (also known as Brt, Dtk, Etk-2, Rek, Rse, Sky, or Tif) is mainly expressed in the brain and Central nervous system (CNS), and is shown to be related to tumorigenesis and tumor cell survival. Therefore, Tyro3 can be used as a target for the identification of therapeutic agents to treat cancer caused by excessive expression of Tyro3 (such as bladder cancer, melanoma, and breast cancer) or to enhance the immune response.

Axl(又稱為Ark、Tyro7或Ufo)表現於正常組織，特別是在骨髓基質、骨髓細胞和免疫細胞(例如：樹突細胞、巨噬細胞和天然殺手細胞)。 Axl會與第I型的干擾素受體共同作用，以增加細胞因子信號傳導抑制因子-1(Suppressor of cytokine signaling，SOCS)和SOCS-3的表現，而有助於終止炎症性類鐸受體(Toll-like receptors TLR)的信號傳導。抑制Axl則有助於恢復炎症性TLR的信號傳導。特別的是，Axl涉及多種腫瘤類型的轉移。在患者的樣品和細胞系中，Axl的表現與遷移和轉移有關。典型的上皮細胞間質轉化(Epithelial-mesenchymal transition，EMT)誘導的基因產物TWIST、SNAIL和SLUG，就是通過Axl的過度表現或是GAS6的刺激而誘導形成(可參考Yu et al.,Journal of Experimental & Clinical Cancer Research,2010,29：119)。TWIST和SNAIL另可刺激Axl的表現，並強化上皮細胞間質轉化，故抑制Axl的表現有助於降低轉移性的增生。另外。Axl具有抵抗標靶治療(Targeted therapeutics)的效果。大部分的癌症研究表明抑制Axl具有廣泛的實用性，並可使腫瘤對標靶治療恢復敏感性。 Axl (also known as Ark, Tyro7 or Ufo) is expressed in normal tissues, especially in bone marrow stromal cells, bone marrow cells and immune cells (eg dendritic cells, macrophages and natural killer cells). Axl will work with type I interferon receptors to increase the performance of cytokine signaling inhibitory factor-1 (Suppressor of cytokine signaling, SOCS) and SOCS-3, and help to stop the inflammatory Duo receptors (Toll-like receptors TLR) signaling. Inhibiting Axl helps to restore the signaling of inflammatory TLRs. In particular, Axl is involved in the metastasis of multiple tumor types. In patient samples and cell lines, Axl performance is related to migration and metastasis. Typical epithelial-mesenchymal transition (EMT) induced gene products TWIST, SNAIL and SLUG are induced by excessive expression of Axl or stimulation of GAS6 (refer to Yu et al., Journal of Experimental & Clinical Cancer Research , 2010 , 29:119). TWIST and SNAIL can also stimulate the performance of Axl and strengthen the transformation of epithelial cells, so inhibiting the performance of Axl helps reduce metastatic hyperplasia. Also. Axl has the effect of resisting targeted therapies. Most cancer studies have shown that inhibiting Axl has a wide range of utility, and can restore the sensitivity of tumors to target therapy.

Mer(又稱為c-Eyk、Mertk、Nyk或Tyro12)幾乎只表現於單核細胞譜系(Monocyte cell lineage)中。Mer在胞葬作用中具重要的作用，所謂的胞葬作用即單核細胞的衍生細胞和上皮細胞清除將程序性死亡的凋亡細胞移除的過程。Mer可在巨噬細胞中起作用，以促進自身抗原的清除、修復受損組織並抑制炎症。在與腫瘤相關的巨噬細胞中，抑制Mer可以增強抵抗腫瘤的免疫力。 Mer (also known as c-Eyk, Mertk, Nyk, or Tyro12) is almost exclusively expressed in the monocyte cell lineage. Mer plays an important role in the burial process. The so-called burial process is the process in which monocyte-derived cells and epithelial cells are cleared to remove apoptotic cells that have undergone apoptosis. Mer can play a role in macrophages to promote self-antigen clearance, repair damaged tissues and suppress inflammation. In tumor-associated macrophages, inhibition of Mer can enhance immunity against tumors.

本發明提供一種使用式(I)化合物，或其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類中的其中一種的實驗方法，以治療與Tyro3、Axl或Mer激酶相關的癌症。 The present invention provides an experimental method using a compound of formula (I), or one of its tautomers, stereoisomers, isotopic isomers, and pharmaceutically acceptable salts to treat Tyro3, Axl, or Mer Kinase-related cancer.

合成式(I)化合物的方法於本領域所熟知。例如：可參考R.Larock,Comprehensive Organic Transformations(2^nd Ed.,VCH Publishers 1999)、P.G.M.Wuts and T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4^th Ed.,John Wiley and Sons 2007)、L.Fieser and M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis(John Wiley and Sons 1994)、L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis(2^nd ed.,John Wiley and Sons 2009)、P.Roszkowski,J.K.Maurin,Z.Czarnocki“Enantioselective synthesis of(R)-(-)-praziquantel(PZQ)”Tetrahedron：Asymmetry 17(2006)1415-1419、L.Hu,S.Magesh,L.Chen,T.Lewis,B.Munoz,L.Wang“Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators”和專利合作條約(Patent Co-operation Treaty，PCT)專利公開第2013/067036號。 Methods of synthesizing compounds of formula (I) are well known in the art. For example: Reference R.Larock, Comprehensive Organic Transformations, PGMWuts and TWGreene, Greene's Protective Groups in Organic Synthesis (4 th Ed, John Wiley and Sons 2007.), L.Fieser and M (2 nd Ed, VCH Publishers 1999.) .Fieser, Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons 1994), L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (2 ^nd ed., John Wiley and Sons 2009 ), P. Roszkowski, JKMaurin, Z.Czarnocki " Enantioselective synthesis of (R)-(-)-praziquantel (PZQ) " Tetrahedron: Asymmetry 17 ( 2006 ) 1415-1419, L.Hu, S. Magesh, L. Chen, T. Lewis, B. Munoz , L. Wang " Direct inhibitors of keap1-nrf2 interaction as antioxidant inflammation modulators " and Patent Cooperation Treaty (Patent Co-operation Treaty, PCT) Patent Publication No. 2013/067036.

式(I)中的化合物可抑制RTK激酶，於下述實施例2中，先使用體外測定法篩選，例如Axl激酶測定法和Mer激酶測定法。隨後再以本領域悉知的體內測定法去評估。被選擇的化合物會再進一步於疾病相關功效模型和不良反應模型中進行測試，以驗證其功效。根據測試結果，可決定合適的劑量範圍和給藥途徑。 The compound of formula (I) can inhibit RTK kinase. In Example 2 below, first screening using in vitro assays, such as Axl kinase assay and Mer kinase assay. It is then evaluated using in vivo assays known in the art. The selected compounds will be further tested in disease-related efficacy models and adverse reaction models to verify their efficacy. Based on the test results, the appropriate dosage range and route of administration can be determined.

所屬技術領域的通常知識者在根據上述描述後，無需進一步詳細說明，即可最大程度地利用本發明。因此，下述具體實施例(即實施例1至3)僅用以解釋說明，本發明並不僅限於上述實施例。本文引用的所有出版物均通過引用整體併入。 Those of ordinary skill in the art can use the present invention to the fullest extent without further detailed description based on the above description. Therefore, the following specific embodiments (ie, Embodiments 1 to 3) are only for explanation, and the present invention is not limited to the above embodiments. All publications cited herein are incorporated by reference in their entirety.

於特定實施例中，實施例1詳述了製備特定中間物以及112個可以式(I)表示的示範化合物的方法，以及化合物的特性分析。實施例2和3詳述了檢測化合物所使用的標準方法。 In the specific examples, Example 1 details the preparation of specific intermediates and 112 exemplary compounds that can be represented by formula (I), and the analysis of the characteristics of the compounds. Examples 2 and 3 detail the standard methods used to detect compounds.

請參閱下表1所示，表1列舉了112個可以式(I)表示的示範化合物的結構以及特性分析。 Please refer to Table 1 below. Table 1 lists the structure and characteristics of 112 exemplary compounds represented by formula (I).

上述112個示範化合物是根據下述方法製備而得。 The above 112 exemplary compounds were prepared according to the following methods.

除了上述化合物之外，其餘材料皆為市售可得。反應中所使用的無水環境是以火焰乾燥玻璃器皿，再通以氬氣或氮氣進行冷卻。若無特別說明，下述的反應皆是在氬氣或氮氣的環境下進行，並於Merck所提供預先塗有矽膠60 F254的玻璃背板(5公分×10公分)上以薄層層析(Thin-layer chromatography)進行分析監測。將示範化合物滴入包含濃度為0.3%(w/v)茚三酮以及濃度為3%(v/v)的醋酸的正丁醇溶液，或是濃度為2.5%磷鉬酸(w/v)的乙醇溶液後，以熱槍燒乾。接著，於一紫外光燈(波長為254奈米)下觀察色彩層析譜(Chromatogram)的結果。反應中所使用的溶劑在使用前先在氬氣或氮氣環境下乾燥。舉例來說，四氫呋喃、甲苯和二氯甲烷是以乾燥分子篩管柱(廠牌：LC technology solution Inc.，型號：5A)乾燥，二甲基甲醯胺是以氫化鈣乾燥或直接購買市售的無水二甲基甲醯胺。產物是通過快速層析來純化和分離，使用拋棄式矽膠管柱(廠牌：RediSep，規格：20-40/40-60微米)以及可重複使用的逆相管柱(廠牌：RediSep，規格：20-40微米，型號：C18)。洗滌液系統的濃度是以體積/體積表示。化合物另以核磁共振儀(廠牌：Bruker，型號：AVIII-400MHz)測量¹³C和¹H的核磁共振(Nuclear Magnetic Resonance，NMR)圖譜，以氯仿-d或二甲基亞碸-d₆與氘代甲醇作為溶劑，以四甲基矽烷(Tetramethylsilane，TMS)(δ、0.00ppm)作為內標。化學位移(Chemical shift)以四甲基矽烷的百萬分率(Part per million，ppm)為基準，表示與四甲基矽烷的差值，並以δ作為單位表示。其中，s表示單峰(singlet)、br s表示寬峰(broad singlet)、d表示二重峰(doublet)、t表示三重峰(triplet)、q表示四重峰(quartet)、dd表示雙二重峰(doublet of doublet)、dt表示雙三重峰(doublet of triplet)而m表示多重峰(multiplet)。耦合常數(J)是以赫茲為單位。電噴射質譜(Electrospray mass spectra，ESMS)是通過質譜儀(廠牌：Thermo，型號：LTQ XL)紀錄而得，並以質量/電荷(m/z)表示。 Except for the above compounds, the rest of the materials are commercially available. The anhydrous environment used in the reaction is to flame dry the glassware, and then pass argon or nitrogen for cooling. Unless otherwise specified, the following reactions are carried out in an argon or nitrogen environment, and thin-layer chromatography (5 cm × 10 cm) on a glass back plate (5 cm × 10 cm) pre-coated with silicone 60 F254 provided by Merck Thin-layer chromatography) for analysis and monitoring. Drop the demonstration compound into a solution of n-butanol containing ninhydrin at a concentration of 0.3% (w/v) and acetic acid at a concentration of 3% (v/v), or phosphomolybdic acid at a concentration of 2.5% (w/v) After the ethanol solution, burn it with a heat gun. Next, the color chromatogram (Chromatogram) was observed under an ultraviolet light (wavelength: 254 nm). The solvent used in the reaction is dried in an argon or nitrogen environment before use. For example, tetrahydrofuran, toluene, and dichloromethane are dried on a dry molecular sieve column (brand: LC technology solution Inc., model: 5A), and dimethylformamide is dried on calcium hydride or directly purchased commercially. Anhydrous dimethylformamide. The product is purified and separated by flash chromatography using a disposable silicone column (brand: RediSep, specifications: 20-40/40-60 microns) and a reusable reverse phase column (brand: RediSep, specifications) : 20-40 microns, model: C18). The concentration of the washing liquid system is expressed in volume/volume. The compound was measured with ¹³ C and ¹ H nuclear magnetic resonance (Nuclear Magnetic Resonance, NMR) spectra with a nuclear magnetic resonance apparatus (brand: Bruker, model: AVIII-400MHz), and then with chloroform-d or dimethyl sulfoxide-d ₆ and Deuterated methanol was used as the solvent, and Tetramethylsilane (TMS) (δ, 0.00 ppm) was used as the internal standard. The chemical shift is based on the parts per million (ppm) of tetramethylsilane, and represents the difference from tetramethylsilane, and is expressed in units of δ. Among them, s represents a singlet (singlet), br s represents a broad peak (broad singlet), d represents a doublet (doublet), t represents a triplet (triplet), q represents a quartet (quartet), dd represents a double two Doublet of doublet, dt means doublet of triplet and m means multiplet. The coupling constant (J) is in hertz. Electrospray mass spectrometry (ESMS) is recorded by a mass spectrometer (brand: Thermo, model: LTQ XL) and is expressed in mass/charge (m/z).

式(I)中的化合物是以下列化學反應式合成製備而得：

The compound in formula (I) is synthesized by the following chemical reaction formula:

實施例1：式(I)中的化合物的合成Example 1: Synthesis of compound in formula (I)

化合物1是以下列化學反應式合成製備而得，式(I)中的其餘化合物皆可以類似的方式合成製備而得。 Compound 1 is synthesized by the following chemical reaction formula, and the remaining compounds in formula (I) can be synthesized by a similar method.

步驟1：5-溴-2,4-二氯-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶的合成Step 1: Synthesis of 5-bromo-2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo-[2,3-d]pyrimidine

在室溫下，於50毫升的二氯甲烷溶液中分散2,6-二氯-7-脫氮嘌呤(3760毫克、20毫莫耳)，並加入N-溴代丁二醯亞胺(N-bromosuccinimide，NBS)(4270毫克、24毫莫耳)。於迴流攪拌2小時後移除二氯甲烷。再使用水和乙酸乙酯萃取剩餘物使之分層。接著，取出有機相後以碳酸氫鈉水溶液洗滌、以硫酸鈉乾燥再於真空環境下濃縮，以獲得中間物。 At room temperature, disperse 2,6-dichloro-7-deazapurine (3760 mg, 20 mmol) in 50 mL of dichloromethane solution, and add N-bromobutanediimide (N -bromosuccinimide, NBS) (4270 mg, 24 mmol). After stirring at reflux for 2 hours, dichloromethane was removed. The residue was extracted with water and ethyl acetate to separate the layers. Next, the organic phase was taken out, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, and concentrated under vacuum to obtain an intermediate.

配製分散有叔丁醇鉀(4488毫克、40毫莫耳)的四氫呋喃溶液50毫升，降溫至0℃後與中間物混合並攪拌30分鐘。接著，加入2-(三甲基矽基)乙氧基甲基氯(5002毫克、30毫莫耳)，並於室溫狀態下攪拌兩小時。然後，加入水中止反應、加入乙酸乙酯進行萃取並以硫酸鈉乾燥有機相，濃縮後以乙酸乙酯和己烷作為沖提液，於矽膠管柱中層析純化獲得產率為76%的無色固體產物，即為5-溴-2,4-二氯-7-((2-(三甲基乙基矽基)乙氧烷基)甲基)-7H-吡咯並-[2,3-d]嘧啶。特性分析：¹H NMR(500MHz,CDCl₃)：δ 7.41(s,1H),5.57(s,2H),3.53(t,J=8.3Hz,2H),0.92(t,J=8.3Hz,2H),0.03(s,9H)；Mass(ESI)m/z 396.19[M+H⁺]。 Prepare 50 ml of a tetrahydrofuran solution in which potassium tert-butoxide (4488 mg, 40 mmol) is dispersed. After cooling to 0°C, mix with the intermediate and stir for 30 minutes. Next, 2-(trimethylsilyl)ethoxymethyl chloride (5002 mg, 30 mmol) was added and stirred at room temperature for two hours. Then, water was added to stop the reaction, ethyl acetate was added for extraction, and the organic phase was dried with sodium sulfate. After concentration, ethyl acetate and hexane were used as eluents, and purified by chromatography on a silica gel column to obtain a colorless 76% yield The solid product is 5-bromo-2,4-dichloro-7-((2-(trimethylethylsilyl)ethoxyalkyl)methyl)-7H-pyrrolo-[2,3- d] Pyrimidine. Characteristic analysis: ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.41 (s, 1H), 5.57 (s, 2H), 3.53 (t, J=8.3 Hz, 2H), 0.92 (t, J=8.3 Hz, 2H ), 0.03 (s, 9H); Mass (ESI) m/z 396.19 [M+H ⁺ ].

步驟2：5-溴-2-氯-4-(2-(甲氧基乙氧基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶的合成Step 2: 5-bromo-2-chloro-4-(2-(methoxyethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo -[2,3-d] Synthesis of pyrimidine

配製分散有叔丁醇鉀(1306毫克、11.6毫莫耳)的乾燥四氫呋喃溶液10毫升，於0℃的氮氣環境下加入2-甲氧基乙醇(487毫克、6.4毫莫耳)，於室溫下攪拌混合物30分鐘。接著，加入溶有5-溴-2,4-二氯-7-((2-(三甲基甲矽烷基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶(2311毫克、5.8毫莫耳)的四氫呋喃無水溶液5毫升，並於室溫下攪拌兩小時。待反應完成後，加入水中止反應，於真空環境下去除有機溶劑後，加入乙酸乙酯進行多次萃取。並將萃取獲得的有機相合併，以飽和食鹽水洗滌後，加入無水硫酸鈉乾燥再過濾，將過濾後收集的液體於減壓環境下移除濾液。以乙酸乙酯和己烷作為沖提液，再於矽膠管柱中層析純化獲得產率為61%的淡黃色油狀產物，即為5-溴-2-氯-4-(2-(甲氧基乙氧基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶。特性分析：¹H NMR(500MHz,CDCl3)：δ 7.17(s,1H),5.51(s,2H),4.69(t,J=4.5Hz,2H),3.84(t,J=4.5Hz,2H),3.51(d,J=8.0Hz,2H),3.48(s,3H),0.91(t,J=8.0Hz,2H),-0.04(s,9H)；Mass(ESI)m/z 436.38[M+H⁺]。 Prepare 10 ml of dry tetrahydrofuran solution dispersed with potassium tert-butoxide (1306 mg, 11.6 mmol), add 2-methoxyethanol (487 mg, 6.4 mmol) under nitrogen at 0°C, at room temperature The mixture was stirred for 30 minutes. Next, add 5-bromo-2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (2311 mg, 5.8 mmol) of tetrahydrofuran in 5 ml of anhydrous solution was stirred at room temperature for two hours. After the reaction was completed, water was added to stop the reaction. After the organic solvent was removed in a vacuum environment, ethyl acetate was added for multiple extractions. The organic phases obtained by extraction were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate collected after filtration was removed under reduced pressure. Ethyl acetate and hexane were used as eluents, and then purified by chromatography on a silica gel column to obtain a light yellow oily product with a yield of 61%, that is, 5-bromo-2-chloro-4-(2-(methyl Oxyethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo-[2,3-d]pyrimidine. Characteristic analysis: ¹ H NMR(500MHz ,CDCl3): δ 7.17(s,1H),5.51(s,2H),4.69(t,J=4.5Hz,2H),3.84(t,J=4.5Hz,2H),3.51(d,J=8.0 Hz, 2H), 3.48 (s, 3H), 0.91 (t, J = 8.0 Hz, 2H), -0.04 (s, 9H); Mass (ESI) m/z 436.38 [M+H ⁺ ].

步驟3：N-(4-(2-氯-4-(2-甲氧基乙氧基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶-5-基)苯基)-2,5-二氟苯磺醯胺的合成Step 3: N-(4-(2-chloro-4-(2-methoxyethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole Synthesis of Pyro-[2,3-d]pyrimidin-5-yl)phenyl)-2,5-difluorobenzenesulfonamide

於溶有5-溴-2-氯-4-(2-(甲氧基乙氧基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶(437毫克、1.0毫莫耳)的1,4-二惡烷脫氣溶液中，加入(4-((2,5-二氟苯基)磺醯胺基)苯基)硼酸頻哪醇酯(435毫克、1.1毫莫耳)、乙酸鈀(II)(5毫克、0.02毫莫耳)、(2-雙環己基膦-2',4',6'-三異丙基聯苯)(XPhos)(19毫克、0.04毫莫耳)和碳酸銫(977毫克、3.0毫莫耳)。將上述溶液加熱迴流至起始物反應完畢，於真空環境下移除有機溶劑，並以乙酸乙酯進行多次萃取。合併萃取後的有機相並以飽和食鹽水洗滌、以無水硫酸鈉乾燥再過濾。將過濾後收集的液體於減壓環境下蒸發，再以乙酸乙酯和己烷作為沖提液，於矽膠管柱中層析純化獲得產率為41%的淡黃色油狀產物，即為N-(4-(2-氯-4-(2-甲氧基乙氧基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶-5-基)苯基)-2,5-二氟苯磺醯胺。特性分析：¹H NMR(500MHz,CDCl₃)：δ 7.59(d,J=8.5Hz,2H),7.56-7.58(m,1H),7.17-7.23(m,3H),7.15(d,J=8.5Hz,2H),7.00(s,1H),5.57(s,2H),4.62(t,J=4.5Hz,2H),3.68(t,J=4.5Hz,2H),3.54(t,J=8.2Hz,2H),3.37(s,3H),0.92(t,J=8.2Hz,2H),-0.05(s,9H)；Mass(ESI)m/z 625.53[M+H⁺]。 Dissolved in 5-bromo-2-chloro-4-(2-(methoxyethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo -[2,3-d]pyrimidine (437 mg, 1.0 mmol) in 1,4-dioxane degassed solution, add (4-((2,5-difluorophenyl)sulfonamide )Phenyl)boronic acid pinacol ester (435 mg, 1.1 mmol), palladium (II) acetate (5 mg, 0.02 mmol), (2-biscyclohexylphosphine-2',4',6'- Triisopropylbiphenyl) (XPhos) (19 mg, 0.04 mmol) and cesium carbonate (977 mg, 3.0 mmol). The above solution was heated to reflux until the starting material was reacted and removed under vacuum. The organic solvent was extracted multiple times with ethyl acetate. The extracted organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtered liquid was evaporated under reduced pressure and then treated with acetic acid Ethyl acetate and hexane were used as eluents and purified by chromatography on a silica gel column to obtain a pale yellow oily product with a yield of 41%, namely N-(4-(2-chloro-4-(2-methoxy Ethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo-[2,3-d]pyrimidin-5-yl)phenyl)-2, 5-Difluorobenzenesulfonamide. Characteristic analysis: ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.59 (d, J=8.5 Hz, 2H), 7.56-7.58 (m, 1H), 7.17-7.23 (m, 3H), 7.15(d, J=8.5Hz, 2H), 7.00(s, 1H), 5.57(s, 2H), 4.62(t, J=4.5Hz, 2H), 3.68(t, J=4.5Hz, 2H), 3.54(t, J=8.2Hz, 2H), 3.37(s, 3H), 0.92(t, J=8.2Hz, 2H), -0.05(s, 9H); Mass(ESI) m/z 625.53 [M+H ⁺ ].

步驟4：2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)苯磺醯胺的合成Step 4: 2,5-difluoro-N-(4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl )Phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzene Synthesis of Sulfadiamide

於溶有N-(4-(2-氯-4-(2-甲氧基乙氧基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並-[2,3-d]嘧啶-5-基)苯基)-2,5-二氟苯磺醯胺(140毫克、0.224毫莫耳)的1,4-二惡烷脫氣溶液中，加入4-((4-甲基哌嗪-1-基)甲基)苯胺(51毫克、0.246毫莫耳)、乙酸鈀(II)(1毫克、0.004毫莫耳)、(2-雙環己基膦-2',6'-二甲氧基聯苯)(SPhos)(3毫克、0.008毫莫耳)和碳酸銫(146毫克、0.448毫莫耳)。將上述溶液於150W的微波輻射下加熱20分鐘，於真空環境下移除有機溶劑，並以乙酸乙酯進行多次萃取。合併萃取後的有機相並以飽和食鹽水洗滌、以無水硫酸鈉乾燥並過濾。將過濾後收集的液體於減壓環境下蒸發，再以二氯甲烷和甲醇作為沖提液，於矽膠管柱中層析純化獲得產率為41%的淡黃色固體產物，即為2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)苯磺醯胺。特性分析：¹H NMR(500MHz,CDCl₃)：δ 7.63(d,J=8.5Hz,2H),7.61(d,J=8.3Hz,2H),7.53-7.57(m,1H),7.25(d,J=8.3Hz,2H),7.14-7.21(m,2H),7.11(d,J=8.5Hz,2H),6.96(s,2H),5.51(s,2H),4.55(t,J=4.6Hz,2H),3.69(t,J=4.6Hz,2H),3.56(t,J=8.3Hz,2H),3.47(s,2H),3.37(s,3H),2.48(br,8H),2.29(s,3H),0.92(t,J=8.3Hz,2H),-0.09(s,9H)；Mass(ESI)m/z 794.58,397.79[M+H⁺]。 Dissolved in N-(4-(2-chloro-4-(2-methoxyethoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole Phenyl-[2,3-d]pyrimidin-5-yl)phenyl)-2,5-difluorobenzenesulfonamide (140 mg, 0.224 mmol) in 1,4-dioxane degassed solution , Add 4-((4-methylpiperazin-1-yl)methyl)aniline (51 mg, 0.246 mmol), palladium(II) acetate (1 mg, 0.004 mmol), (2-bicyclo Hexylphosphine-2',6'-dimethoxybiphenyl) (SPhos) (3 mg, 0.008 mmol) and cesium carbonate (146 mg, 0.448 mmol). The above solution was heated under microwave irradiation at 150 W for 20 minutes, the organic solvent was removed in a vacuum environment, and extraction was performed with ethyl acetate multiple times. The extracted organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The liquid collected after filtration was evaporated under reduced pressure, and then dichloromethane and methanol were used as eluents, and purified by chromatography on a silica gel column to obtain a pale yellow solid product with a yield of 41%, that is, 2,5 -Difluoro-N-(4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino )-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzenesulfonamide. Characteristic analysis: ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.63 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.3 Hz, 2H), 7.53-7.57 (m, 1H), 7.25 (d ,J=8.3Hz,2H),7.14-7.21(m,2H),7.11(d,J=8.5Hz,2H),6.96(s,2H),5.51(s,2H),4.55(t,J= 4.6Hz, 2H), 3.69(t, J=4.6Hz, 2H), 3.56(t, J=8.3Hz, 2H), 3.47(s, 2H), 3.37(s, 3H), 2.48(br, 8H) , 2.29 (s, 3H), 0.92 (t, J=8.3 Hz, 2H), -0.09 (s, 9H); Mass (ESI) m/z 794.58, 397.79 [M+H ⁺ ].

步驟5：2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3]-d]嘧啶-5-基)苯基)苯磺酰胺的合成Step 5: 2,5-difluoro-N-(4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl )Phenyl)amino)-7H-pyrrolo[2,3]-d]pyrimidin-5-yl)phenyl)benzenesulfonamide

將溶有2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4- 甲基哌嗪-1-基)甲基)苯基)胺基)-7-((2-(三甲基矽基)乙氧基)甲基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)苯磺醯胺(43毫克、0.054毫莫耳)和四丁基氟化銨(0.54毫升、1M)的四氫呋喃溶液，加熱迴流至起始物反應完畢。於真空環境下移除有機溶劑，並將剩餘物倒入1N的氫氧化納水溶液中，並以乙酸乙酯進行多次萃取。合併萃取後的有機相，以飽和食鹽水洗滌、再以無水硫酸鈉乾燥並過濾。將過濾後收集的液體於減壓環境下蒸發，再以二氯甲烷和甲醇作為沖提液，於矽膠管柱中層析純化獲得產率為33%的白色固體產物，即為2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)苯磺酰胺。特性分析：¹H NMR(500MHz,MeOD)：δ 7.69(d,J=8.5Hz,2H),7.58(d,J=8.5Hz,2H),7.54-7.57(m,1H),7.30-7.37(m,2H),7.20(d,J=8.5Hz,2H),7.12(d,J=8.5Hz,2H),6.98(s,1H),4.54(t,J=4.5Hz,2H),3.69(t,J=4.5Hz,2H),3.47(s,2H),3.34(s,3H),2.50(br,8H),2.28(s,3H)；Mass(ESI)m/z 664.31[M+H⁺]。 2,5-difluoro-N-(4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl )Phenyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzene A solution of sulfonamide (43 mg, 0.054 mmol) and tetrabutylammonium fluoride (0.54 mL, 1M) in tetrahydrofuran was heated to reflux until the reaction of the starting material was completed. The organic solvent was removed under vacuum, and the residue was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate several times. The extracted organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The liquid collected after filtration was evaporated under reduced pressure, and then dichloromethane and methanol were used as eluents, and purified by chromatography on a silica gel column to obtain a white solid product with a yield of 33%, that is, 2,5- Difluoro-N-(4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzenesulfonamide. Characteristic analysis: ¹ H NMR (500MHz, MeOD): δ 7.69 (d, J=8.5Hz, 2H), 7.58 (d, J=8.5Hz, 2H), 7.54-7.57(m, 1H), 7.30-7.37( m, 2H), 7.20(d, J=8.5Hz, 2H), 7.12(d, J=8.5Hz, 2H), 6.98(s, 1H), 4.54(t, J=4.5Hz, 2H), 3.69( t,J=4.5Hz,2H),3.47(s,2H),3.34(s,3H),2.50(br,8H),2.28(s,3H); Mass(ESI)m/z 664.31[M+H ⁺ ].

實施例2：式(I)的化合物於體外試驗時抑制活性的效果評估Example 2: Evaluation of the inhibitory activity of compounds of formula (I) in vitro

以下將詳述實施例1所合成的化合物所測試之體外受體酪胺酸激酶試驗。 The in vitro receptor tyrosine kinase test tested by the compound synthesized in Example 1 will be described in detail below.

1.Axl激酶試驗1. Axl kinase test

通過放大化學螢光親和均相檢測(Amplified Luminescent Proximity Homogeneous Assay Screen，AlphaScreen)(PerkinElmer，6760620M)，可測試式(I)中化合物抑制Axl激酶的效果。標準試驗方法是將1奈克(ng)的重組Axl激酶(SignalChem)和3至10奈克的poly-GT生物素(Cisbio)溶於25微升的試驗緩衝液中。25微升的試驗緩衝液中包括40μM的ATP(Sigma)、10mM的離子緩衝液(MOPs，Sigma，pH值為7.0，M-1254)、0.21mM的乙二胺四乙酸(EDTA)(Sigma E-6758)、0.5%(重量百分比)的甘油(J.T Baker 2136-1)、 1毫克/毫升的牛血清白蛋白(Bio-Rad 500-0007)、0.01%(重量百分比)的2-巰基乙醇(BDH 441433A)以及0.001%(重量百分比)的聚氧乙烯月桂醇(Brij35)(Sigma P1254)。於30℃的溫度下反應30分鐘，最後加入5微升、50mM的EDTA以終止反應。反應產物使用AlphaScreen試劑進行分析，並使用高通量多功能盤式分析儀(Enspire Alpha)(PerkinElmer)來計數。分析數值是以兩重複之八個序列稀釋濃度的測定結果，再利用線性回歸軟體(GraphPad Prism 4，GraphPad Software Inc.)分析出抑制劑的效果。 By the amplified chemical fluorescence affinity homogeneous detection (Amplified Luminescent Proximity Homogeneous Assay Screen, AlphaScreen) (PerkinElmer, 6760620M), the compound of formula (I) can be tested for its effect on inhibiting Axl kinase. The standard test method is to dissolve 1 nanogram (ng) of recombinant Axl kinase (SignalChem) and 3 to 10 nanograms of poly-GT biotin (Cisbio) in 25 microliters of test buffer. 25 μl of test buffer includes 40 μM ATP (Sigma), 10 mM ion buffer (MOPs, Sigma, pH 7.0, M-1254), 0.21 mM ethylenediaminetetraacetic acid (EDTA) (Sigma E -6758), 0.5% (weight percent) of glycerin (JT Baker 2136-1), 1 mg/ml bovine serum albumin (Bio-Rad 500-0007), 0.01% (wt%) 2-mercaptoethanol (BDH 441433A) and 0.001% (wt%) polyoxyethylene lauryl alcohol (Brij35) ( Sigma P1254). The reaction was carried out at a temperature of 30°C for 30 minutes, and finally 5 µl of 50 mM EDTA was added to terminate the reaction. The reaction products were analyzed using AlphaScreen reagents and counted using a high-throughput multi-function disc analyzer (Enspire Alpha) (PerkinElmer). The analysis value is the measurement result of the dilution concentration of two series of eight replicates, and then the effect of the inhibitor is analyzed using linear regression software (GraphPad Prism 4, GraphPad Software Inc.).

2.Mer激酶試驗2. Mer kinase test

通過放大化學發光親和均相檢測(AlphaScreen)(PerkinElmer，6760620M)，可測試式(I)中一些化合物抑制Mer激酶的效果。標準試驗方法是將2奈克的重組Mer激酶(SignalChem)以及5奈克的poly-GT生物素(Cisbio)溶於25微升的試驗緩衝液中。25微升的試驗緩衝液中包括10μM的ATP(Sigma)、8mM的兩性離子緩衝液(MOPs，Sigma，pH值為7.0，M-1254)、0.2mM的乙二胺四乙酸(EDTA)(Sigma E-6758)、0.5%(重量百分比)的甘油(J.T Baker 2136-1)、0.1毫克/毫升的牛血清白蛋白(Bio-Rad 500-0007)、0.01%(重量百分比)的2-巰基乙醇(BDH 441433A)、0.001%(重量百分比)的聚氧乙烯月桂醇(Brij35)(Sigma P1254)、10mM的氯化鎂以及10mM的氯化錳。在30℃的溫度下反應30分鐘，最後加入5微升、50mM的EDTA以終止反應。反應產物使用AlphaScreen試劑進行分析，並使用高通量多功能盤式分析儀(Enspire Alpha)(PerkinElmer)來計數。分析數值是以兩重複之序列稀釋濃度的測定結果，再利用線性回歸軟體(GraphPad Prism 4，GraphPad Software Inc.)分析出抑制劑的效果。 By amplifying chemiluminescence affinity homogeneous detection (AlphaScreen) (PerkinElmer, 6760620M), some compounds of formula (I) can be tested for their inhibitory effect on Mer kinase. The standard test method is to dissolve 2 ng of recombinant Mer kinase (SignalChem) and 5 ng of poly-GT biotin (Cisbio) in 25 μl of test buffer. 25 μl of test buffer includes 10 μM ATP (Sigma), 8 mM zwitterionic buffer (MOPs, Sigma, pH 7.0, M-1254), 0.2 mM ethylenediaminetetraacetic acid (EDTA) (Sigma E-6758), 0.5% (weight percent) glycerin (JT Baker 2136-1), 0.1 mg/ml bovine serum albumin (Bio-Rad 500-0007), 0.01% (weight percent) 2-mercaptoethanol (BDH 441433A), 0.001% (weight percent) polyoxyethylene lauryl alcohol (Brij35) (Sigma P1254), 10 mM magnesium chloride, and 10 mM manganese chloride. The reaction was carried out at a temperature of 30°C for 30 minutes, and finally 5 microliters of 50 mM EDTA was added to terminate the reaction. The reaction products were analyzed using AlphaScreen reagents and counted using a high-throughput multi-function disc analyzer (Enspire Alpha) (PerkinElmer). The analysis value is the result of the determination of the concentration of the serial dilution in duplicate, and then the effect of the inhibitor was analyzed using linear regression software (GraphPad Prism 4, GraphPad Software Inc.).

3.Met激酶試驗3. Met kinase test

通過放大化學發光親和均相檢測(AlphaScreen)(PerkinElmer， 6760620M)，可測試式(I)中一些化合物抑制Met激酶的效果。標準試驗方法是將1奈克的重組Met激酶(SignalChem)、3奈克的poly-GT生物素(Cisbio)溶於25微升的試驗緩衝液中。25微升的試驗緩衝液中包括10μM的ATP(Sigma)、8mM的兩性離子緩衝液(MOPs，Sigma，pH值為7.0，M-1254)、0.2mM的乙二胺四乙酸(EDTA)(Sigma E-6758)、0.5%(重量百分比)的甘油(J.T Baker 2136-1)、0.1毫克/毫升的牛血清白蛋白(Bio-Rad 500-0007)、0.01%(重量百分比)的2-巰基乙醇(BDH 441433A)、0.001%(重量百分比)的聚氧乙烯月桂醇(Brij35)(Sigma P1254)、10mM的氯化鎂以及10mM的氯化錳。在30℃的溫度下反應30分鐘，最後加入5微升、50mM的EDTA以終止反應。反應產物使用AlphaScreen試劑進行分析，並使用高通量多功能盤式分析儀(Enspire Alpha)(PerkinElmer)來計數。分析數值是以兩重複之序列稀釋濃度的測定結果，再利用線性回歸軟體(GraphPad Prism 4，GraphPad Software Inc.)分析出抑制劑的效果。 Amplified chemiluminescence affinity homogeneous detection (AlphaScreen) (PerkinElmer, 6760620M), which can test the effect of some compounds of formula (I) in inhibiting Met kinase. The standard test method is to dissolve 1 ng of recombinant Met kinase (SignalChem) and 3 ng of poly-GT biotin (Cisbio) in 25 μl of test buffer. 25 μl of test buffer includes 10 μM ATP (Sigma), 8 mM zwitterionic buffer (MOPs, Sigma, pH 7.0, M-1254), 0.2 mM ethylenediaminetetraacetic acid (EDTA) (Sigma E-6758), 0.5% (weight percent) glycerin (JT Baker 2136-1), 0.1 mg/ml bovine serum albumin (Bio-Rad 500-0007), 0.01% (weight percent) 2-mercaptoethanol (BDH 441433A), 0.001% (weight percent) polyoxyethylene lauryl alcohol (Brij35) (Sigma P1254), 10 mM magnesium chloride, and 10 mM manganese chloride. The reaction was carried out at a temperature of 30°C for 30 minutes, and finally 5 microliters of 50 mM EDTA was added to terminate the reaction. The reaction products were analyzed using AlphaScreen reagents and counted using a high-throughput multi-function disc analyzer (Enspire Alpha) (PerkinElmer). The analysis value is the result of the determination of the concentration of the serial dilution in duplicate, and then the effect of the inhibitor was analyzed using linear regression software (GraphPad Prism 4, GraphPad Software Inc.).

試驗結果test results

相較於抑制Met激酶的活性，式(I)中的化合物更傾向於抑制Axl激酶和Mer激酶的活性，而且程度上具有明顯的差別。以下結果將以半抑制濃度(Half maximal inhibitory concentration，IC₅₀)表示。IC₅₀值是反應或結合效果降低至一半時抑制劑的濃度。詳細結果列於下表2。 Relative to inhibiting the activity of Met kinase, the compound of formula (I) is more inclined to inhibit the activity of Axl kinase and Mer kinase, and there is a significant difference in the degree. The following results will be expressed in half maximal inhibitory concentration (IC ₅₀ ). The IC ₅₀ value is the concentration of the inhibitor when the reaction or binding effect is reduced to half. The detailed results are listed in Table 2 below.

更精確地來說明，對於Axl激酶方面，本發明112個化合物中有89個化合物的IC₅₀值低於100nM；對於Mer激酶方面，本發明112個化合物中有22個化合物的IC₅₀值低於100nM，其中還包含著代表IC₅₀值低於30nM的評價“A”，代表IC₅₀值介於30nM至100nM的評價“B”，代表IC₅₀值介於100nM至400nM的評價“C”時，以及IC₅₀值介於400nM至1μM的評價“D”。若IC₅₀值大於1μM時，則以評價“E”來表示。 More precisely described, for Axl kinase aspect, the compounds of the present invention, 112 have IC ₅₀ values of less than 10OnM compound 89; Mer for kinase aspect, the compounds of the present invention, 112 have IC ₅₀ values of compound is less than 22 100nM, which also includes an evaluation "A" representing an IC ₅₀ value of less than 30 nM, an evaluation "B" representing an IC ₅₀ value between 30 nM and 100 nM, and an evaluation "C" representing an IC ₅₀ value between 100 nM and 400 nM, And the evaluation "D" with an IC ₅₀ value between 400 nM and 1 μM. If the IC ₅₀ value is greater than 1 μM, it is indicated by the evaluation “E”.

根據表2的結果，式(I)的化合物可選擇性且有效的抑制Axl激酶和Mer活性。而式(I)的化合物對於TAM家族受體受體酪胺酸激酶的專一抑制活性並無法預期，將可應用於治療與TAM激酶相關的疾病。 According to the results in Table 2, the compound of formula (I) can selectively and effectively inhibit Axl kinase and Mer activities. However, the specific inhibitory activity of the compound of formula (I) on TAM family receptor receptor tyrosine kinase is not expected, and it will be applicable to the treatment of diseases related to TAM kinase.

實施例3：式(I)的化合物與現有技術中結構相似化合物的比較Example 3: Comparison of compounds of formula (I) with structurally similar compounds in the prior art

挑選出本發明實施例中的化合物25和化合物22，與現有技術中涵蓋的化合物A和化合物B進行體外激酶抑制活性比較。 Compound 25 and compound 22 in the examples of the present invention were selected and compared with compound A and compound B covered in the prior art for in vitro kinase inhibitory activity.

如下表3所示，化合物25和化合物22的結構與化合物A和化合物B的結構相似，其差異在於：本發明的化合物25和化合物22具有特定的取代基。具體來說，化合物25和化合物22中的苯基是通過亞甲基連接胺基，並非如化合物A和化合物B中的苯基是通過羰基連接胺基。 As shown in Table 3 below, the structures of compound 25 and compound 22 are similar to the structures of compound A and compound B, and the difference is that compound 25 and compound 22 of the present invention have specific substituents. Specifically, the phenyl groups in compound 25 and compound 22 are connected to the amine group through a methylene group, not as the phenyl groups in compound A and compound B are connected to the amine group through a carbonyl group.

由表3的結果可得知，相較於現有技術中涵蓋的化合物A和化合物B，本發明的化合物25和化合物22展現出非預期地高Axl激酶抑制活性，其抑制效果為化合物A和化合物B的五倍或五倍以上。 From the results of Table 3, it can be seen that, compared with Compound A and Compound B covered in the prior art, Compound 25 and Compound 22 of the present invention exhibit unexpectedly high Axl kinase inhibitory activity, and the inhibitory effect is Compound A and Compound Five times or more of B.

實施例4：評估式(I)的化合物對於生長停滯特異性基因6(Growth arrest specific 6，Gas6)配體所誘導蛋白激酶B(Protein kinase B，PKB/AKT)磷酸化的細胞內抑制效果Example 4: Evaluation of the intracellular inhibitory effect of the compound of formula (I) on phosphorylation of protein kinase B (PKB/AKT) induced by growth arrest specific 6 (Gas6) ligand

Gas6/TAM訊息傳遞路徑在多種癌症的發展中扮演種重要的角色，例如：急性骨髓性白血病(Acute myeloid leukemia，AML)、急性淋巴性白血病(Acute lymphoblastic leukemia，ALL)、神經鞘瘤、神經膠質瘤、甲狀腺癌、卵巢癌、肺癌、胃癌、***癌、腎細胞癌、乳腺癌和黑色素瘤。一般來說，Gas6/TAM訊息通路會促使癌症的進展，且Gas6/TAM的表現也與癒後不佳有關(Wu et al.,Cell Death & Disease,vol.8,page e2700,2017)。 Gas6/TAM signaling pathway plays an important role in the development of various cancers, such as: acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), schwannomas, gliomas Tumor, thyroid cancer, ovarian cancer, lung cancer, gastric cancer, prostate cancer, renal cell carcinoma, breast cancer and melanoma. In general, the Gas6/TAM signaling pathway will promote cancer progression, and the performance of Gas6/TAM is also associated with poor recovery (Wu et al., Cell Death & Disease , vol. 8, page e2700, 2017 ).

由實施例2中挑選出有效化合物，以西方點墨法(Western blotting)評估化合物對於細胞內Gas6配體所誘導AKT磷酸化的抑制效果。在西方點墨法中，H1299 NSCLC細胞先在無血清RPMI-1640培養基中過夜培養。於試驗當天，在六孔板中將20萬個細胞先以化合物預處理二小時後，再用濃度為100奈克/毫升的Gas6配體刺激30分鐘。接著，加入等量之兩倍十二烷基硫酸鈉(2×SDS)樣品緩衝液進行全細胞的樣品萃取。所得的蛋白質再以十二烷基硫酸鈉聚丙烯醯胺凝膠電泳(Sodium dodecyl sulfate polyacrylamide gel electrophoresis，SDS-PAGE)電泳分離後，並轉漬至聚偏二氟乙烯(PVDF)膜上。蛋白質的表現量依據免疫點墨法標準試驗流程，以使用一級抗體和二級抗體來檢測。抗磷酸化AKT[P-AKT(Ser473)的抗體和具HRP連接的抗兔IgG二級抗體都是購自於Cell Signaling Technology。抗肌動蛋白的抗體購自Millipore。免疫點墨法的實驗結果是使用最高靈敏度底物(SuperSignal TM West Femto Maximum Sensitivity Substrate，Thermo)通過化學發光來顯現，並以ChemiDocTM MP成像系統(Bio-Rad)進行檢測。西方點墨法所測得的色帶強度(Band intensity)也利用ChemiDocTM MP成像系統進行定量，以僅有配體處理的控制組為基準，將對應於藥物處理的色帶強度進行相對性比較。每一藥物濃度的抑制百分率是依下列公式計畫所得：抑制百分率(%)=(1-相對色帶強度)×100。 An effective compound was selected from Example 2, and the inhibitory effect of the compound on intracellular Gas6 ligand-induced AKT phosphorylation was evaluated by Western blotting. In the Western blot method, H1299 NSCLC cells are first cultured overnight in serum-free RPMI-1640 medium. On the day of the experiment, 200,000 cells were pretreated with the compound for two hours in a six-well plate, and then stimulated with Gas6 ligand at a concentration of 100 ng/ml for 30 minutes. Next, an equal amount of twice the sodium dodecyl sulfate (2×SDS) sample buffer was added to perform whole cell sample extraction. The obtained protein was separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene fluoride (PVDF) membrane. Protein table The current amount is based on the standard test procedure of the immunodot method, using primary antibodies and secondary antibodies for detection. Anti-phospho-AKT [P-AKT (Ser473) antibodies and HRP-linked anti-rabbit IgG secondary antibodies were purchased from Cell Signaling Technology. Anti-actin antibodies were purchased from Millipore. The results of the immunospot method were visualized by chemiluminescence using the highest sensitivity substrate (SuperSignal™ West Femto Maximum Sensitivity Substrate, Thermo) and detected with the ChemiDoc™ MP imaging system (Bio-Rad). The band intensity measured by the Western dot blot method was also quantified using the ChemiDocTM MP imaging system, and the band intensity corresponding to the drug treatment was compared relative to the control group with only ligand treatment. The percentage of inhibition for each drug concentration is calculated according to the following formula: percentage of inhibition (%) = (1-relative ribbon intensity) × 100.

式(I)中被選擇的化合物，在100nM的藥物濃度處理下，可抑制50%以上因Gas6配體所誘導之AKT磷酸化，具體化合物列於下表4中。 The compound selected in formula (I) can inhibit the phosphorylation of AKT induced by Gas6 ligand by more than 50% at the drug concentration of 100 nM. The specific compounds are listed in Table 4 below.

其他實施例Other embodiments

本發明說明書中揭示的所有特徵可以任何方式結合，且說明書中的每一特徵可被具有相同、相當或相似效果的另一特徵取代。除了前述揭示的內容之外，每一揭示的特徵僅為一系列相似特徵中的其中一個舉例。 All features disclosed in the specification of the present invention may be combined in any manner, and each feature in the specification may be replaced by another feature having the same, equivalent, or similar effect. In addition to the foregoing disclosure, each disclosed feature is only an example of a series of similar features.

並且，根據上述內容，所屬技術領域具有通常知識者可輕易得知本發明的基本特徵，並且可在不悖離其精神和範圍的情況下，根據不同用途和情況對本發明進行各種改變和修飾，且仍在本發明的保護範圍之內。 Moreover, according to the above, those with ordinary knowledge in the technical field can easily learn the basic features of the present invention, and can make various changes and modifications to the present invention according to different uses and situations without departing from the spirit and scope of the invention. And still within the protection scope of the present invention.

[實施例的有益效果] [Beneficial effect of embodiment]

以上所公開的內容僅為本發明的優選可行實施例，並非因此侷限本發明的申請專利範圍，所以凡是運用本發明說明書內容所做的等效技術變化，均包含於本發明的申請專利範圍內。 The content disclosed above is only a preferred and feasible embodiment of the present invention, and therefore does not limit the scope of the patent application of the present invention, so all equivalent technical changes made by using the contents of the description of the present invention are included in the scope of the patent application of the present invention. .

Claims

一種化合物，以式(I)表示：

或是為式(I)的互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類；其中，R¹是選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；L是選自於由下列所構成的群組：氧原子、硫原子、亞胺基和芳香基；環A(

)是選自於由下列所構成的群組：

其中，R^a和R^b中的其中一個是Q，R^a和R^b中的另一個是R²；Q是選自於由下列所構成的群組：氫原子、鹵素、OR⁵、OCH₂Ar、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；R⁵和R⁶是各自獨立選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基，或是 R⁵和R⁶相互連接形成碳數為3至8的環烷基或碳數為3至8的雜環烷基；R⁷是選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；其中，Ar是選自於由下列所構成的群組：苯並二噁烷基、吲唑基、異喹啉基、異噁唑基、萘基、噁二唑基、苯基、吡啶基、嘧啶基、吡啶酮基和喹啉基；前述Ar中的每一環上選擇性取代有1、2、3或4個取代基，所述取代基各自獨立選自於由下列所構成的群組：碳數為1至4的烷氧基、碳數為1至4的烷氧羰基、碳數為1至4的烷氧羰基胺基、碳數為1至4的烷基、(碳數為1至4的烷)羰基、(碳數為1至4的烷基)磺醯基、醯胺基、胺基羰基、胺基羰基(碳數為1至3的烷基)、-(CH₂)_qCO₂-(碳數為1至4的烷基)、-(CH₂)_qOH、羧基、氰基、甲醯基、鹵基、碳數為1至4的鹵代烷基、碳數為1至4的鹵代烷氧基、硝基、選擇性取代有一個氰基的苯基、選擇性取代有一個鹵基的苯氧基、苯羰基、吡咯基和四氫哌喃基；q為0、1、2、3或4；其中，所述碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基各自選擇性取代有一或多個鹵素、OR⁵、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為1至8的烷氧基、碳數為2至8的烯基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；其中，每一R²是獨立選自於由下列所構成的群組：鹵素、氫原子、羥基、甲醇基、氰基、三氟甲基、甲烷基、甲氧基、三氟甲氧基和二甲胺基；其中，R³是選自於由下列所構成的群組：氫原子、碳數為1至4的烷基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；其中，R⁴是選自於由下列所構成的群組：氫原子、氰基、碳數為1至4的烷基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；其中，每一W和V各自獨立為氮原子或CR⁸，R⁸是選自於由下列所構成的群組：氫原子、鹵素、OR⁵、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁶、NR⁵SO₂R⁷、碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基；其中，G是選自於由下列所構成的群組：鹵素、OR⁵、氰基、疊氮基、硝基、NH(R⁹)、N(R⁹)(R¹⁰)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂(R⁵)、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基；每一R⁹和R¹⁰各自獨立選自於由下列所構成的群組：碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基，或是R⁹和R¹⁰相互連接形成碳數為3至8的雜環烷基；每一碳數為1至8的烷基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基，選擇性取代有一或多個由下列所構成的群組：鹵素、OR⁵、氰基、疊氮基、硝基、N(R⁵)(R⁶)、N(R⁵)CO(R⁷)、C(O)R⁵、C(O)OR⁵、C(O)N(R⁵)(R⁶)、SO₂R⁵、SO₂N(R⁵)(R⁶)、SOR⁵、SR⁵、NR⁵SO₂R⁷、碳數為1 至8的烷基、碳數為1至8的烷氧基、碳數為2至8的烯基、碳數為2至8的炔基、碳數為3至8的環氧基、碳數為3至8的雜環烷基、芳香基和雜芳基；其中，R⁵和R⁶是各自獨立選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為1至8的雜環烷基、芳香基和雜芳基，或是R⁵和R⁶相互連接形成碳數為3至8的環烷基或碳數為3至8的雜環烷基；R⁷是選自於由下列所構成的群組：氫原子、碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基。 A compound, represented by formula (I):

Or tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts of formula (I); wherein R ¹ is selected from the group consisting of: hydrogen atom, carbon Alkyl group having 1 to 8 carbon atoms, cycloalkyl group having 3 to 8 carbon atoms, heterocycloalkyl group having 3 to 8 carbon atoms, aromatic group and heteroaryl group; L is selected from the group consisting of Group: oxygen atom, sulfur atom, imino group and aromatic group; ring A(

) Is selected from the group consisting of:

Wherein, R ^a and R ^b is one of the Q, the other R ^a and R ^b is R ^2; Q is selected from the group consisting of the following: a hydrogen atom, a halogen, OR ^5, OCH ₂ Ar, cyano, azido, nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O )N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , alkyl group with carbon number 1 to 8 , Alkenyl having 2 to 8 carbons, alkynyl having 2 to 8 carbons, cycloalkyl having 3 to 8 carbons, heterocycloalkyl having 1 to 8 carbons, aromatic groups and heteroaryl groups ; R ⁵ and R ⁶ are each independently selected from the group consisting of a hydrogen atom, an alkyl group having a carbon number of 1 to 8, a cycloalkyl group having a carbon number of 3 to 8, and a carbon number of 3 to 8; Heterocyclic alkyl, aromatic and heteroaryl groups, or R ⁵ and R ⁶ are connected to form a cycloalkyl group having 3 to 8 carbon atoms or a heterocycloalkyl group having 3 to 8 carbon atoms; R ⁷ is selected From the group consisting of: hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, heterocycloalkyl groups having 3 to 8 carbon atoms, aromatic groups and hetero groups Aryl; wherein, Ar is selected from the group consisting of benzodioxanyl, indazolyl, isoquinolinyl, isoxazolyl, naphthyl, oxadiazolyl, phenyl, Pyridyl, pyrimidinyl, pyridone, and quinolinyl; each ring in the aforementioned Ar is optionally substituted with 1, 2, 3, or 4 substituents, each of which is independently selected from the group consisting of Group: alkoxy group having 1 to 4 carbon atoms, alkoxycarbonyl group having 1 to 4 carbon atoms, alkoxycarbonylamine group having 1 to 4 carbon atoms, alkyl group having 1 to 4 carbon atoms, (carbon C1-C4 alkyl) carbonyl, (C1-C4 alkyl) sulfonyl, amidyl, aminocarbonyl, aminocarbonyl (C1-C3 alkyl), -( CH ₂ ) _q CO ₂ -(alkyl having 1 to 4 carbons), -(CH ₂ ) _q OH, carboxyl, cyano, methanoyl, halo, haloalkyl having 1 to 4 carbons, carbon 1 to 4 haloalkoxy, nitro, phenyl optionally substituted with one cyano, phenoxy optionally substituted with one halo, phenylcarbonyl, pyrrolyl and tetrahydropiperanyl; q is 0, 1, 2, 3 or 4; wherein, the alkyl group having 1 to 8 carbons, the alkenyl group having 2 to 8 carbons, the alkynyl group having 2 to 8 carbons, and the carbon number being 3 to 8 Cycloalkyl, C1-C8 heterocycloalkyl, aryl and heteroaryl are each optionally substituted with one or more halogen, OR ⁵ , cyano, azido, nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , alkyl having 1 to 8 carbons, alkoxy having 1 to 8 carbons, alkenyl having 2 to 8 carbons, cycloalkyl having 3 to 8 carbons, Heterocycloalkyl, aryl and heteroaryl having 1 to 8 carbon atoms; wherein each R ² is independently selected from the group consisting of halogen, hydrogen atom, hydroxyl group, methanol group, cyano group , Trifluoromethyl, methyl, methoxy, trifluoromethoxy and dimethylamino; where R ³ is selected from the group consisting of: hydrogen atom, carbon number 1 to 4 Alkyl, cycloalkyl having 3 to 8 carbons, heterocycloalkyl having 1 to 8 carbons, aryl and heteroaryl; wherein R ⁴ is selected from the group consisting of: hydrogen Atom, cyano, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 8 carbons, heterocycloalkyl having 1 to 8 carbons, aromatic and heteroaryl; where each W And V are each independently a nitrogen atom or CR ⁸ , R ⁸ is selected from the group consisting of: hydrogen atom, halogen, OR ⁵ , cyano, azido, nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N (R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁶ , NR ⁵ SO ₂ R ⁷ , alkyl having 1 to 8 carbons, alkenyl having 2 to 8 carbons, alkyne having 2 to 8 carbons Group, cycloalkyl group having 3 to 8 carbon atoms, heterocycloalkyl group having 1 to 8 carbon atoms, aromatic group and heteroaryl group; wherein, G is selected from the group consisting of halogen, OR ⁵ , cyano, azido, nitro, NH(R ⁹ ), N(R ⁹ )(R ¹⁰ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O) OR ⁵ , C(O)N(R ⁵ )(R ⁶ ), SO ₂ (R ⁵ ), SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , carbon Alkenyl groups having 2 to 8 carbon atoms, alkynyl groups having 2 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, heterocycloalkyl groups having 3 to 8 carbon atoms, aromatic groups and heteroaryl groups; R ⁹ and R ¹⁰ are each independently selected from the group consisting of alkyl groups having 1 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, and heterocycloalkanes having 3 to 8 carbon atoms Group, aromatic group and heteroaryl group, or R ⁹ and R ¹⁰ are connected to each other to form a heterocyclic alkyl group having 3 to 8 carbon atoms; each alkyl group having 1 to 8 carbon atoms and 2 to 8 carbon atoms Alkenyl, alkynyl having 2 to 8 carbons, cycloalkyl having 3 to 8 carbons, heterocycloalkyl having 3 to 8 carbons, aromatic and heteroaryl groups, optionally substituted with one or more Group consisting of: halogen, OR ⁵ , cyano, azido, nitro, N(R ⁵ )(R ⁶ ), N(R ⁵ )CO(R ⁷ ), C(O)R ⁵ , C(O)OR ⁵ , C(O) N(R ⁵ )(R ⁶ ), SO ₂ R ⁵ , SO ₂ N(R ⁵ )(R ⁶ ), SOR ⁵ , SR ⁵ , NR ⁵ SO ₂ R ⁷ , alkyl having 1 to 8 carbons, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 epoxy, C 3-8 hetero Cycloalkyl, aryl, and heteroaryl; wherein R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen atom, alkyl group having 1 to 8 carbon atoms, and carbon atom having 3 to 8 cycloalkyl groups, heterocyclic alkyl groups having 1 to 8 carbon atoms, aromatic groups and heteroaryl groups, or R ⁵ and R ⁶ are connected to form cycloalkyl groups having 3 to 8 carbon atoms or 3 carbon atoms Heterocycloalkyl to 8; R ⁷ is selected from the group consisting of hydrogen atom, alkyl having 1 to 8 carbons, cycloalkyl having 3 to 8 carbons, and carbon 3 Heterocycloalkyl, aromatic and heteroaryl groups up to 8.

如申請專利範圍第1項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，G是N(R⁹)(R¹⁰)，每一R⁹和R¹⁰各自獨立選自於由下列所構成的群組：碳數為1至8的烷基、碳數為3至8的環烷基、碳數為3至8的雜環烷基、芳香基和雜芳基，或是R⁹和R¹⁰共同連接形成碳數為3至8的雜環烷基。 The compound as described in item 1 of the patent application scope, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein G is N(R ⁹ )(R ¹⁰ ) , Each of R ⁹ and R ^{10 is} independently selected from the group consisting of alkyl groups having 1 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, and heterocycles having 3 to 8 carbon atoms Cycloalkyl, aryl, and heteroaryl, or R ⁹ and R ^{10 are} joined together to form a heterocycloalkyl having 3 to 8 carbon atoms.

如申請專利範圍第1項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，L為氧原子。 The compound as described in item 1 of the patent application scope, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein L is an oxygen atom.

如申請專利範圍第2項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，G是N(R⁹)(R¹⁰)或碳數為3至8的雜環烷基。 The compound as described in item 2 of the patent application scope, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein G is N(R ⁹ )(R ¹⁰ ) Or heterocycloalkyl having 3 to 8 carbon atoms.

如申請專利範圍第4項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，G是碳數為3至8的雜環烷基。 The compound as described in item 4 of the patent application, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein G is a heterocyclic ring having 3 to 8 carbon atoms alkyl.

如申請專利範圍第5項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，碳數為3至8的雜環烷基是一五環結構或一六環結構。 Compounds as described in item 5 of the patent application, or tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts thereof, wherein the heterocyclic alkyl group having 3 to 8 carbon atoms Is a five-ring structure or a six-ring structure.

如申請專利範圍第6項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，G是

，且G選擇性取代有一或多個碳數為1至8的烷基；Y是氧原子、-NR或-CR'R"；每一R、R'和R"各自獨立選自於由下列所構成的群組：氫原子、羥基、胺基或碳數為1至8的烷基。 The compound as described in item 6 of the patent application scope, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein G is

, And G is optionally substituted with one or more alkyl having 1 to 8; Y is an oxygen atom, -NR or -CR 'R "; each R, R' and R" are each independently selected from the group consisting of the following The formed group: hydrogen atom, hydroxyl group, amine group or alkyl group having 1 to 8 carbon atoms.

如申請專利範圍第7項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，Y是-NR，R是氫原子或碳數為1至8的烷基；或者Y是-CR'R"，R、R'和R"各自獨立選自於氫原子、羥基、胺基或碳數為1至8的烷基。 The compound as described in item 7 of the patent application, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein Y is -NR and R is a hydrogen atom or carbon alkyl having 1 to 8; or Y is -CR 'R ", R, R ' and R" are each independently selected from a hydrogen atom, a hydroxyl group, amine or alkyl having 1 to 8.

如申請專利範圍第8項所述的化合物，或是其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，其中，所述化合物為

，W和V各自獨立為氮原子或CR⁸，R⁸是選自於由下列所構成的群組；氫原子、鹵素、OR⁵、N(R⁵)(R⁶)或碳數為1至8的烷基。 The compound as described in item 8 of the patent application, or its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts, wherein the compound is

, W and V are each independently a nitrogen atom or CR ⁸ , R ⁸ is selected from the group consisting of: hydrogen atom, halogen, OR ⁵ , N(R ⁵ )(R ⁶ ) or carbon number from 1 to 8 alkyl.

如申請專利範圍第1項所述的化合物，其中，所述化合物是選自於由下列所構成的群組：2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3]-d]嘧啶-5-基)苯基)苯磺醯胺、2,5-二氟-N-(4-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)苯磺醯胺、2,5-二氟-N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)苯磺醯胺、N-(4-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶唑-5-基)苯基)甲磺醯胺、4-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯磺醯胺、4-(2-((4-((4- 胺基哌啶-1-基)甲基)苯基)胺基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯磺醯胺、4-(4-甲氧基-2-((4-(嗎啉代甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N，N-二甲基苯磺醯胺、4-(2-((2-氟-4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯磺醯胺、5-(2-氟-4-((4-甲基吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、(3-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-))苯基)甲醇、5-(2-氟-4-((3-甲基吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(3-氟苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺)、5-(2-氟苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-氯苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯甲醯胺、4-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯磺醯胺、4-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、3-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-5-(2-氟-4-(吡啶-2-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-5-(4-甲氧基苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-5-(3-甲氧基苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(4-甲氧基-2-((6-((4-甲基哌嗪-1-基) 甲基)吡啶-3-基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N，N-二甲基苯磺醯胺、N,N-二甲基-4-(2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-4-(甲硫基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯磺醯胺、3-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯甲酸甲酯、5-(2,4-二氟苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、N-(4-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)-1,5-二甲基-1H-吡唑-3-甲醯胺、4-(4-甲氧基-2-((6-((4-甲基哌嗪-1-基)甲基)吡啶-3-基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、4-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、N-(3-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)-1,5-二甲基-1H-吡唑-3-甲醯胺、5-(2,4-二氟苯基)-4-甲氧基-N-(4-((4-甲基哌啶-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-N-(4-((4-甲基哌啶-1-基)甲基)苯基)-5-(鄰甲苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-N-(4-((4-甲基哌啶-1-基)甲基)苯基)-5-(間甲苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-N-(4-((4-甲基哌啶-1-基)甲基)苯基)-5-(對甲苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-(嘧啶-2-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌啶-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(3-(二甲基胺基)苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氯苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(3-氯苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-氟苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-5-(2-氟-4-(嘧啶-2-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺、3-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N二甲基苯甲醯、4-(4-甲氧基-2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯磺醯胺、4-(2-((6-((4-乙基哌嗪-1-基)甲基)吡啶-3-基)胺基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、5-(6-氟吡啶-3-基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(芐氧基)-3-甲氧基苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(芐氧基)-2-氟苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(3,4,5-三甲氧基苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(2-((4-((4-乙基哌嗪-1-基)甲基)苯基)胺基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、5-(2-氟-4-甲基苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(3-氯-4-氟苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,1，3-d]嘧啶-2-胺、5-(3-氯-4-氟苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-4-((四氫呋喃-2-基)甲氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺)、5-(2,4-二氟苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2，3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-N4-乙基-N2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]]嘧啶-2,4-二胺、4-(環戊基氧基)-5-(2,4-二氟苯基)-N-(4-((4-甲基哌嗪-1-基)甲基) 苯基)-7H-吡咯並[2,3]-d]嘧啶-2-胺、5-(4-(芐氧基)-3-甲氧基苯基)-N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-5-(4-((2-甲氧基乙氧基)甲氧基)苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(3-氯-4-氟苯基)-N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-4-甲氧基-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-4-乙氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、2-氟-5-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N-甲基苯甲醯胺、N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-4-甲氧基-5-(3-甲氧基-4-((2-甲氧基乙氧基)甲氧基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-胺基嘧啶-5-基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-4-((1-甲氧基丙-2-基)氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(2-甲氧基乙氧基)-5-(2-甲基苯並[d]噁唑-6-基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、6-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-2-甲基喹唑啉-4(1H)-酮、4,4'-(2-((4-((4-甲基哌啶-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-4,5-二基)二(N,N-二甲基苯磺醯胺)、5-(2-甲基苯並[d]噁唑-6-基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-4-((四氫呋喃-2-基)甲氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺、1-((3-氟-4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯氧基)甲基)吡啶-2(1H)-酮、5-(2,4-二氟苯基)-4-異丙氧基-N-(4-(4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(芐氧基)-3-甲氧基苯基)-4-甲氧基-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3]-d] 嘧啶-2-胺、5-(3-氯-4-氟苯基)-N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-4-(2-甲氧基乙氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-甲氧基-5-(2-甲基苯並[d]噁唑-6-基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(3-甲氧基-4-((6-甲基吡啶-3-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-N2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N4-((四氫-2H-哌喃-4-基)甲基)-7H-吡咯並[2,3-d]嘧啶-2,4-二胺、5-(2,4-二氟苯基)-N2-(4-((4-甲基哌嗪-1-基)甲基)苯基)-N4-(四氫-2H-哌喃-4-基)-7H-吡咯並[2,3-d]嘧啶-2,4-二胺、N-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)-1,5-二甲基-1H-吡唑-3-甲醯胺、5-(3-氯-4-氟苯基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-4-((四氫呋喃-2-基)甲氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2,4-二氟苯基)-4-(2-甲氧基乙氧基)-N-(3-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯磺醯胺、5-(2,4-二氟苯基)-N-(4-((二甲基胺基)甲基)苯基)-4-(2-甲氧基乙氧基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)芐腈、4-(4-甲氧基-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯甲腈、4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(4-(三氟甲氧基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(4-(三氟甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-氟苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2- 胺、N,N-二乙基-4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯磺醯胺、5-(4-((3,5-二甲基哌啶-1-基)磺醯基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(4-(嗎啉代)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(異丙基磺醯基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(芐氧基)-2-氟苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並並[2,3-d]嘧啶-2-胺、3-氟-4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-N,N-二甲基苯磺醯胺、5-(2-氟-4-(吡啶-2-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-(吡啶-4-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(氮雜環丁烷-1-基磺醯基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-(吡啶-3-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、3-氟-4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯酚、4-(2-甲氧基乙氧基)-5-(1-甲基-1H-吲唑-5-基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(4-(哌啶-1-基磺醯基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-((4-甲氧基吡啶-3-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2- 胺、5-(2-氟-4-((5-甲氧基吡啶-3-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)-2-甲基-2,3-二氫異噻唑並[4,5-b]吡啶1,1-二氧化物、4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(4-((4-甲基哌嗪-1-基)磺醯基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-((6-甲基吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-((6-氟吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-((5-甲基吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、2-(4-(4-(2-甲氧基乙氧基)-2-((4-((4-甲基哌嗪-1-基)甲基)苯基)胺基)-7H-吡咯並[2,3-d]嘧啶-5-基)苯基)丙-2-醇、5-(2-氟-4-(嘧啶-2-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-((3-甲基-4-(2,2,2-三氟乙氧基)吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-(吡啶-2-基甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌啶-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、4-(2-甲氧基乙氧基)-N-(4-((4-甲基哌嗪-1-基)甲基)苯基)-5-(4-(吡啶-2-基甲氧基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、5-(2-氟-4-((3-甲基吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-N-(4-((4-甲基-1-基)甲基)苯基)-7H-吡咯並[2,3-d]嘧啶-2-胺、N-(4-((4-乙基哌嗪-1-基)甲基)苯基)-5-(2-氟-4-((3-甲基吡啶-2-基)甲氧基)苯基)-4-(2-甲氧基乙氧基)-7H-吡咯並[2,3-d] 嘧啶-2-胺，及其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類。 The compound according to item 1 of the patent application scope, wherein the compound is selected from the group consisting of: 2,5-difluoro-N-(4-(4-(2-methoxy Ethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3]-d]pyrimidine-5- Yl)phenyl)benzenesulfonamide, 2,5-difluoro-N-(4-(4-methoxy-2-((4-((4-methylpiperidin-1-yl)methyl )Phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzenesulfonamide, 2,5-difluoro-N-(4-(4-(2 -Methoxyethoxy)-2-((4-((4-methylpiperidin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine -5-yl)phenyl) benzenesulfonamide, N-(4-(4-methoxy-2-((4-((4-methylpiperidin-1-yl)methyl)phenyl) Amino)-7H-pyrrolo[2,3-d]pyrimidazol-5-yl)phenyl)methanesulfonamide, 4-(4-methoxy-2-((4-((4-methyl Piperidin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethylbenzenesulfonamide, 4- (2-((4-((4- Aminopiperidin-1-yl)methyl)phenyl)amino)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethyl Toluenesulfonamide, 4-(4-methoxy-2-((4-(morpholinomethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl )-N,N-dimethylbenzenesulfonamide, 4-(2-((2-fluoro-4-((4-methylpiperidin-1-yl)methyl)phenyl)amino)- 4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethylbenzenesulfonamide, 5-(2-fluoro-4-((4-methyl Pyridin-2-yl)methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)benzene Group)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, (3-(4-methoxy-2-((4-((4-methylpiperazin-1-yl)methyl Yl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-))phenyl)methanol, 5-(2-fluoro-4-((3-methylpyridine-2- Yl)methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-amine, 5-(3-fluorophenyl)-4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl Yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine), 5-(2-fluorophenyl)-4-methoxy-N-(4-((4-methyl Piperazine-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(4-chlorophenyl)-4-methoxy-N- (4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(4-methoxy-2 -((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N- Dimethylbenzamide, 4-(4-methoxy-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo [2,3-d]pyrimidin-5-yl)-N,N-dimethylbenzenesulfonamide, 4-(4-methoxy-2-((4-((4-methylpiperazine- 1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, 3-(4-methoxy-2-((4-(( 4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, N-(4-((4-B Piperazine-1-yl)methyl)phenyl)-5-(2-fluoro-4-(pyridin-2-ylmethoxy)phenyl)-4-(2-methoxyethoxy) -7H-pyrrolo[2,3-d]pyrimidine-2-amine, 4-methoxy-5-(4-methoxyphenyl)-N-(4-((4-methylpiperazine- 1- Yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-methoxy-5-(3-methoxyphenyl)-N-(4-( (4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(4-methoxy-2-((6 -((4-methylpiperazin-1-yl) Methyl)pyridin-3-yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethylbenzenesulfonamide, N,N-dimethyl -4-(2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-4-(methylthio)-7H-pyrrolo[2,3- d)pyrimidin-5-yl)benzenesulfonamide, 3-(4-methoxy-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino) -7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzoic acid methyl ester, 5-(2,4-difluorophenyl)-4-methoxy-N-(4-((4 -Methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, N-(4-(4-methoxy-2-(( 4-((4-methylpiperidin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1,5- Dimethyl-1H-pyrazole-3-carboxamide, 4-(4-methoxy-2-((6-((4-methylpiperazin-1-yl)methyl)pyridine-3- Yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, 4-(4-methoxy-2-((4-((4-methylpiperidin-1 -Yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, N-(3-(4-methoxy-2-((4- ((4-methylpiperidin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)-1,5-dimethyl Yl-1H-pyrazole-3-carboxamide, 5-(2,4-difluorophenyl)-4-methoxy-N-(4-((4-methylpiperidin-1-yl) Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-methoxy-N-(4-((4-methylpiperidin-1-yl)methyl )Phenyl)-5-(o-tolyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-methoxy-N-(4-((4-methylpiperidine- 1-yl)methyl)phenyl)-5-(m-tolyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-methoxy-N-(4-((4 -Methylpiperidin-1-yl)methyl)phenyl)-5-(p-tolyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4 -(Pyrimidin-2-ylmethoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperidin-1-yl)methyl)benzene Group)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(3-(dimethylamino)phenyl)-4-methoxy-N-(4-((4 -Methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-chlorophenyl)-4-methoxy- N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5- (3-chlorophenyl)-4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d] Pyrimidine-2-amine, 5-(4-fluorophenyl)-4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrole And [2,3-d]pyrimidin-2-amine, N-(4-((4-B Piperazine-1-yl)methyl)phenyl)-5-(2-fluoro-4-(pyrimidin-2-ylmethoxy)phenyl)-4-(2-methoxyethoxy) -7H-pyrrolo[2,3-d]pyrimidin-2-amine, 3-(4-methoxy-2-((4-((4-methylpiperazin-1-yl)methyl)benzene (Yl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N dimethyl benzoyl, 4-(4-methoxy-2-((4-( (4-methylpiperidin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzenesulfonamide, 4-(2-( (6-((4-ethylpiperazin-1-yl)methyl)pyridin-3-yl)amino)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine-5- Group) phenol, 5-(6-fluoropyridin-3-yl)-4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H- Pyrrolo[2,3-d]pyrimidin-2-amine, 5-(4-(benzyloxy)-3-methoxyphenyl)-4-methoxy-N-(4-((4- Methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2,4-difluorophenyl)-N-(4 -((4-ethylpiperazin-1-yl)methyl)phenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(4-( Benzyloxy)-2-fluorophenyl)-4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2, 3-d)pyrimidine-2-amine, 4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5-(3,4,5- Trimethoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(2-((4-((4-ethylpiperazin-1-yl)methyl)benzene Yl)amino)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, 5-(2-fluoro-4-methylphenyl)-4-methoxy -N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(3-chloro -4-fluorophenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo [2,1,3-d]pyrimidine-2-amine, 5-(3-chloro-4-fluorophenyl)-4-methoxy-N-(4-((4-methylpiperazine-1 -Yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2,4-difluorophenyl)-N-(4-((4-methyl Piperazine-1-yl)methyl)phenyl)-4-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine), 5- (2,4-difluorophenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2,4-difluorophenyl)-N4-ethyl-N2-(4-((4-methylpiperazine-1 -Yl)methyl)phenyl)-7H-pyrrolo[2,3-d]]pyrimidine-2,4-diamine, 4-(cyclopentyloxy)-5-(2,4-difluoro Phenyl)-N-(4-((4-methylpiperazin-1-yl)methyl) Phenyl)-7H-pyrrolo[2,3]-d]pyrimidin-2-amine, 5-(4-(benzyloxy)-3-methoxyphenyl)-N-(4-((4 -Ethylpiperazin-1-yl)methyl)phenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-methoxy-5-(4 -((2-methoxyethoxy)methoxy)phenyl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d)pyrimidine-2-amine, 5-(3-chloro-4-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl) -4-methoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2,4-difluorophenyl)-4-ethoxy-N-(4-(( 4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 2-fluoro-5-(4-methoxy-2- ((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzene Formamide, N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-4-methoxy-5-(3-methoxy-4-((2- Methoxyethoxy)methoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-aminopyrimidin-5-yl)-4-(2 -Methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine , 5-(2,4-Difluorophenyl)-4-((1-methoxyprop-2-yl)oxy)-N-(4-((4-methylpiperazin-1-yl )Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(2-methoxyethoxy)-5-(2-methylbenzo[d] Oxazol-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 6-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[ 2,3-d)pyrimidin-5-yl)-2-methylquinazolin-4(1H)-one, 4,4'-(2-((4-((4-methylpiperidin-1 -Yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-4,5-diyl)bis(N,N-dimethylbenzenesulfonamide), 5- (2-methylbenzo[d]oxazol-6-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4-((tetrahydrofuran-2 -Yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 1-((3-fluoro-4-(4-(2-methoxyethoxy)-2 -((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy)methan Base) Pyridin-2(1H)-one, 5-(2,4-difluorophenyl)-4-isopropoxy-N-(4-(4-methylpiperazin-1-yl)methyl)benzene Group)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(4-(benzyloxy)-3-methoxyphenyl)-4-methoxy-N-(4 -((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3]-d] Pyrimidine-2-amine, 5-(3-chloro-4-fluorophenyl)-N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-4-(2- (Methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-methoxy-5-(2-methylbenzo[d]oxazol-6-yl) -N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(3-methoxy 4-((6-Methylpyridin-3-yl)methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazine -1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2,4-difluorophenyl)-N2-(4-((4 -Methylpiperazin-1-yl)methyl)phenyl)-N4-((tetrahydro-2H-piperan-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidine- 2,4-diamine, 5-(2,4-difluorophenyl)-N2-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-N4-(tetrahydro -2H-piperan-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine, N-(4-(4-(2-methoxyethoxy)- 2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)- 1,5-dimethyl-1H-pyrazole-3-carboxamide, 5-(3-chloro-4-fluorophenyl)-N-(4-((4-methylpiperazin-1-yl )Methyl)phenyl)-4-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2,4-difluorobenzene Group)-4-(2-methoxyethoxy)-N-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3- d) Pyrimidine-2-amine, 4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amine Group)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethylbenzenesulfonamide, 5-(2,4-difluorophenyl)-N-(4 -((Dimethylamino)methyl)phenyl)-4-(2-methoxyethoxy)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(4 -(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3- d)pyrimidin-5-yl)benzonitrile, 4-(4-methoxy-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H -Pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile, 4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl )Methyl)phenyl)-5-(4-(trifluoromethoxy)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(2-methoxy Ethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5-(4-(trifluoromethyl)phenyl)-7H-pyrrolo[ 2,3-d)pyrimidine-2-amine, 5-(4-fluorophenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazine-1 -Yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Amine, N,N-diethyl-4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl )Amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzenesulfonamide, 5-(4-((3,5-dimethylpiperidin-1-yl)sulfonamide Yl)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-2-amine, 4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5 -(4-(morpholino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(4-(isopropylsulfonyl)phenyl)-4-( 2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2- Amine, 5-(4-(benzyloxy)-2-fluorophenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl )Methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 3-fluoro-4-(4-(2-methoxyethoxy)-2-(( 4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N,N-dimethyl Toluenesulfonamide, 5-(2-fluoro-4-(pyridin-2-ylmethoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4- Methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-(pyridin-4-ylmethoxy Yl)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidine-2-amine, 5-(4-(azetidin-1-ylsulfonyl)phenyl)-4-(2-methoxyethoxy)-N-( 4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-(pyridine -3-ylmethoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)- 7H-pyrrolo[2,3-d]pyrimidin-2-amine, 3-fluoro-4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiper Azin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenol, 4-(2-methoxyethoxy)-5- (1-methyl-1H-indazol-5-yl)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3- d) Pyrimidine-2-amine, 4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5-(4 -(Piperidin-1-ylsulfonate (Acyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-((4-methoxypyridin-3-yl)methoxy) Phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3 -d]pyrimidine-2- Amine, 5-(2-fluoro-4-((5-methoxypyridin-3-yl)methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4- ((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(4-(2-methoxyethoxy Yl)-2-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)- 2-methyl-2,3-dihydroisothiazolo[4,5-b]pyridine 1,1-dioxide, 4-(2-methoxyethoxy)-N-(4-(( 4-methylpiperazin-1-yl)methyl)phenyl)-5-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-7H-pyrrolo[2 ,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-((6-methylpyridin-2-yl)methoxy)phenyl)-4-(2-methoxyethoxy Group)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2- Fluoro-4-((6-fluoropyridin-2-yl)methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazine- 1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-((5-methylpyridin-2-yl)methyl Oxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrolo[ 2,3-d)pyrimidine-2-amine, 2-(4-(4-(2-methoxyethoxy)-2-((4-((4-methylpiperazin-1-yl) (Methyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propan-2-ol, 5-(2-fluoro-4-(pyrimidine-2- Methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrole Benzo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl )Methoxy)phenyl)-4-(2-methoxyethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-7H-pyrrole P[[3,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-(pyridin-2-ylmethoxy)phenyl)-4-(2-methoxyethoxy)- N-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, 4-(2-methoxy Ethoxy)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-5-(4-(pyridin-2-ylmethoxy)phenyl)-7H -Pyrrolo[2,3-d]pyrimidin-2-amine, 5-(2-fluoro-4-((3-methylpyridin-2-yl)methoxy)phenyl)-4-(2- Methoxyethoxy Group)-N-(4-((4-methyl-1-yl)methyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine, N-(4-(( 4-ethylpiperazin-1-yl)methyl)phenyl)-5-(2-fluoro-4-((3-methylpyridin-2-yl)methoxy)phenyl)-4-( 2-methoxyethoxy)-7H-pyrrolo[2,3-d] Pyrimidine-2-amine, and its tautomers, stereoisomers, isotopic isomers and pharmaceutically acceptable salts.

一醫藥組成物，其包括如請求項1至10中任一項所述的化合物，或其互變異構物、立體異構物、同位素異構物和藥學可接受的鹽類，以及一藥學可接受的稀釋劑或載體。 A pharmaceutical composition, which includes the compound according to any one of claims 1 to 10, or a tautomer, stereoisomer, isotopic isomer, and pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Accepted diluent or carrier.

如申請專利範圍第11項所述的醫藥組成物，用以治療由Tyro3、Axl和/或Mer激酶介導的疾病或失調，或是用以治療由Tyro3、Axl或Mer突變所介導的病變。 The pharmaceutical composition as described in item 11 of the patent application scope for the treatment of diseases or disorders mediated by Tyro3, Axl and/or Mer kinase, or for the treatment of diseases mediated by Tyro3, Axl or Mer mutations .

一種如請求項11所述的醫藥組成物在製備治療由Tyro3、Axl和/或Mer激酶介導的疾病或失調的藥物中的用途。 Use of a pharmaceutical composition according to claim 11 in the preparation of a medicament for treating a disease or disorder mediated by Tyro3, Axl and/or Mer kinase.

如申請專利範圍第13項所述的用途其中，所述疾病或失調為癌症。 The use according to item 13 of the patent application scope, wherein the disease or disorder is cancer.

如申請專利範圍第14項所述的用途，其中，所述癌症是選自於由下列所構成的群組：肺癌、結腸癌、結直腸癌、乳腺癌、***癌、肝癌、胰腺癌、膀胱癌、胃癌、腎癌、唾液腺癌、卵巢癌、子宮體癌、宮頸癌、口腔癌、皮膚癌、腦癌、淋巴瘤和白血病。 The use according to item 14 of the patent application scope, wherein the cancer is selected from the group consisting of lung cancer, colon cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, bladder Cancer, stomach cancer, kidney cancer, salivary gland cancer, ovarian cancer, uterine body cancer, cervical cancer, oral cancer, skin cancer, brain cancer, lymphoma and leukemia.